Substituted aminoalkylamide derivatives as antagonists of follicle stimulating hormone

ABSTRACT

The present invention is directed to a series of novel substituted aminoalkylamide derivatives, pharmaceutical compositions containing them and their use in the treatment of reproductive disorders and affective conditions. Further, the compounds of the invention are antagonists of follicle stimulating hormone, a hormone associated with the human reproductive system.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. provisional application Serial No. 60/173,139, filed Dec. 27, 1999, the contents of which are hereby incorporated by reference.

FIELD OF THE INVENTION

[0002] This invention relates to novel substituted aminoalkylamide derivatives, pharmaceutical compositions containing them and their use in the treatment of reproductive disorders and affective conditions. The compounds of the invention are antagonists of follicle stimulating hormone, a hormone associated with the human reproductive system.

BACKGROUND OF THE INVENTION

[0003] Follicle stimulating hormone (FSH) belongs to a family of glycoprotein hormones, which includes lutenizing hormone (LH), thyrotropin (TSH) and chorionic gonadotropin (CG). Each of these hormones is composed of two different non-covalently bound subunits termed α and β. Within a species the amino acid sequence of the α subunits for these different hormones is identical, while the hormone specific β subunits exhibit different amino acid sequences (Combarnous, Endocrine Review, 13:670-691 (1992).

[0004] In females, follicle stimulating hormone (FSH) stimulates follicular granulosa cell proliferation in the ovary and impacts synthesis of estrogen, a hormone which is integral to follicular maturation and ovulation. An antagonist of FSH therefore acts to limit proliferation of follicular granulosa cells in the ovary, acting as a contraceptive. The FSH antagonist may also delay the maturation of follicles within the ovary, thereby postponing the maturation of a limited number of follicles in women. Such treatments have the potential for increasing the possibility of natural fertilization and pregnancy later in life.

[0005] Because of the controlling function of FSH on estrogen synthesis, an FSH antagonist may also be effective in the treatment of estrogen related disorders such as uterine fibroids, endometriosis, polycystic ovarian disease, dysfunctional uterine bleeding, breast cancer and ovarian cancer.

[0006] An added advantage for an FSH antagonist would be its specific action on ovarian tissue without impact on peripheral tissues containing estrogen receptors. This would be expected to reduce the side effects associated with estrogen receptor antagonists.

[0007] Because the proliferation of follicular granulosa cells also impacts the health and development of the oocyte, FSH antagonists may be useful in preventing depletion of oocytes, a common side effect of chemotherapy or similar treatments designed to treat rapidly dividing cells.

[0008] In males, follicle stimulating hormone (FSH) is involved in the maturation of sperm cells. More specifically, FSH action in males is directed at the Sertoli cells, which are a recognized target of the hormone and which support the process of sperm maturation (spermatogenesis). FSH antagonists will therefore inhibit sperm maturation without affecting the production of androgens produced from Leydig cells under the control of luteinizing hormone (LH). In addition, FSH receptors have been reported in the epididymis in the male reproductive tract. Thus an FSH antagonist would be expected to affect the viability and motility of sperm by controlling functions of the epididymis.

[0009] FSH antagonists also have the potential to modify the rate of germ cell division in males. Because chemotherapy is known to deplete rapidly dividing cells such as spermatocytes, an FSH antagonist may be useful in a planned chemotherapy regimen to prevent spermatocyte depletion.

[0010] An FSH antagonist used as a female contraceptive could be used in contraceptive formulations alone or in combination with known contraceptive agents such as progesterone receptor modulators, estrogen receptor modulators, or androgen receptor modulators. An FSH antagonist used as a male contraceptive could be used alone or in combination with androgen receptor modulators, progesterone receptor modulators, or with estrogen receptor modulators. In addition, agents that affect the viability or motility or fertilizability of sperm by acting within the female genital tract may also be used in combination with FSH antagonists concomitantly, or as scheduled in a kit that prevents fertilization during the administration of an FSH antagonist. An example of such an agent is nonoxynol-9.

[0011] In recent years, peptide (based) FSH agonists and antagonists have been discovered and developed. Bono, G., et. al., in WO 97/12038 disclose novel amino acid residue peptide useful in stimulating FSH enhancement.

[0012] Amino acid based sulfonamide derivatives have also been developed for the treatment of a variety of conditions and disorders. Dumont, R. in WO 93/05014 discloses sulfonamide derivatives useful as inhibitors of Ca⁺² dependent enzymes.

[0013] The compounds of the present invention are non-peptide antagonists of FSH useful in the treatment of estrogen related disorders such as uterine fibroids, endometriosis, polycystic ovarian disease, dysfunctional uterine bleeding, breast cancer and ovarian cancer; prevention of depletion of oocytes (a common side effect of chemotherapy or similar treatment); female and male contraception; and prevention of spermatocyte depletion.

[0014] Additionally, the generation of chemical libraries on and off solid resins has proven to be a valuable resource for the pharmaceutical industry in their endeavors to discover new drugs using high throughput screening (HTPS) techniques. In creating the libraries, the compounds are ideally synthesized in situ in solution phase or on a solid support. However, relatively simple synthetic methods to produce a diverse collection of such derivatives in situ are often not available.

[0015] Pharmaceutical drug discovery relies heavily on studies of structure-activity relationships wherein the structure of “lead compounds” is typically altered to determine the effect of such alteration on activity. Alteration of the structure of the lead compounds permits evaluation of the effect of the structural alteration on activity.

[0016] Thus, libraries of compounds derived from a lead compound can be created by including derivatives of the lead compound and repeating the screening procedures. In this manner, compounds with the best biological profile, i.e., those that are most active and which have the most ideal pharmacologic and pharmacokinetic properties, can be identified from the initial lead compound.

SUMMARY OF THE INVENTION

[0017] The present invention is directed to compounds of the formula (I)

[0018] wherein

[0019] R¹ and R² are independently selected from the group consisting of hydrogen, C₁-C₆alkyl, C₁-C₆alkylcarbonyl, C₁-C₆perhaloalkyl, phenyl, phenylC₁-C₆alkyl-, phenylcarbonyl-, pyridyl, pyridylC₁-C₆alkyl-, pyridylcabonyl-, thienyl, thienylC₁-C₆alkyl- and thienylcarbonyl, wherein the phenyl, pyridyl or thienyl is optionally substituted with one to three substituents independently selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy or NO₂;

[0020] R³ is selected from the group consisting of hydrogen, C₁-C₆alkyl, C₂-C₄alkenyl and C₂-C₄alkynyl, where the C₁-C₆alkyl is optionally substituted with a phenyl, pyridyl, thienyl or furyl, wherein the phenyl, pyridyl, thienyl or furyl is optionally substituted with one to three substituents independently selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy or NO₂;

[0021] R⁴ is selected from the group consisting of —C₂-C₆alkyl-, -cyclopentyl-, -cylcohexyl-, -cyclohexyl-CH₂—, —CH₂-cyclohexyl-CH₂—, —CH₂-phenyl-CH₂—, —C(O)—CH₂-phenyl-CH₂—, —C(O)—C₁-C₆alkyl- and -cyclohexyl-CH₂-cyclohexyl-;

[0022] where the R⁴ substituent is inserted into the compound of formula (I) from left to right, as defined;

[0023] alternately, R², R³, and R⁴ can be taken together with the two N atoms of the diamine portion of the molecule to form

[0024]  alternately, R³ can be taken together with R² as —C₂-C₃alkyl-, provided that R⁴ is —C₂-C₆alkyl-;

[0025] L is selected from the group consisting of —C₃-C₆cycloalkyl (wherein the cycloalkyl is substituted with R⁵ and R⁶), a bicyclic compound of the form

[0026]  (wherein the point of the attachment of the bicyclic compound is any carbon atom of the alkyl portion and wherein the aromatic portion of the bicyclic compound is optionally substituted with one to three substituents independently selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, NO₂, acetamido, —NH₂, —NH(C₁-C₆alkyl) or —N(C₁-C₆alkyl)₂), and —(CH₂)_(m)—CR⁸R¹R^(6;)

[0027] m is 0 to 3;

[0028] R⁵ is selected from the group consisting of phenyl, naphthyl, (wherein the phenyl and naphthyl may be optionally substituted with one to three substituents independently selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, NO₂, acetamido, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, C₁-C₆alkylcarbonylamino or C₁-C₆alkylsulfonylamino), bicyclo[4.2.0]octa-1,3,5-trienyl, 2,3-dihydro-1H-indolyl, N-methylpyrrolidinyl, 3,4-methylenedioxyphenyl, C₃-C₆cyloalkenyl, (wherein the cycloalkenyl group contains one or two double bonds), a six membered heteroaryl (wherein the six membered heteroaryl contains one to three N atoms), and a five membered heteroaryl (wherein the five membered heteroaryl contains one sulfur, oxygen or nitrogen, optionally contains one to three additional nitrogen atoms); wherein the point of attachment for the five or six membered heteroaryl is a carbon atom; and wherein the five or six membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy or NO₂;

[0029] R⁶ is selected from the group consisting of hydrogen, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₁-C₆alkoxy, hydroxy and phenyl, (wherein the phenyl may be optionally substituted with one to three substituents independently selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl or trifluoromethoxyl); provided that R⁶ may be phenyl only when R⁵ is phenyl;

[0030] R⁸ is selected from the group consisting of hydrogen and C₁-C₆alkyl;

[0031] Z is selected from the group consisting of —SO₂—, —C(═O)—, and —C(═O)N H—;

[0032] p is 0 to 1;

[0033]  is selected from the group consisting of phenyl, naphthyl, quinolinyl, thienyl, and furyl;

[0034] X is selected from the group consisting of halogen, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, NO₂, acetamido, —NH₂, —NH(C₁-C₆alkyl) and —N(C₁-C₆alkyl)₂;

[0035] n is 0 to 3;

[0036] Y is selected from the group consisting of phenyl, —O-phenyl, —NH-phenyl, naphthyl, (wherein the phenyl or naphthyl is optionally substituted with one to three substituents selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, NO₂, cyano, methylthio, acetamido, formyl, -amino, -aminocarbonyl, —NH—C₁-C₆alkyl, —N(C₁-C₆alkyl)₂, —COOH, —COO(C₁-C₆alkyl), —COO(C₁-C₆alkylphenyl), C₁-C₆alkylcarbonylamino, C₁-C6alkylaminocarbonyl, di(C₁-C₆alkyl)aminocarbonyl, aminosulfonyl, C₁-C6alkylaminosulfonyl or di(C₁-C₆alkyl)aminosulfonyl), biphenyl, 3,4-methylenedioxyphenyl, dianthrenyl, dibenzothienyl, phenoxathiinyl, a six membered heteroaryl (wherein the six membered heteroaryl contains one to three nitrogen atoms), and a five membered heteroaryl (wherein the five membered heteroaryl contains one sulfur, oxygen or nitrogen atom, optionally contains one to three additional nitrogen atoms); wherein the point of attachment for the five or six membered heteroaryl is a carbon atom; and wherein the five or six membered heteroaryl is optionally substituted with one to three substituents selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, formyl, NO₂, cyano, methylthio, acetamido, -amino, -aminocarbonyl, —NH C₁-C₆alkyl, —N(C₁-C₆alkyl)₂, —COOH, —COO(C₁-C₆alkyl), or —COO(C₁-C₆alkylphenyl));

[0037] q is 0 to 1;

[0038] provided that when q is 1, n is 0;

[0039] and stereoisomers and pharmaceutically acceptable salts or esters thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0040] The compounds of formula (I) that comprise this invention may be prepared using a process wherein the compound is synthesized on a solid support resin, followed by cleavage of the compound from the resin support, as a final isolation step. The various substituents described in formula (I) may be present initially on the reagents employed to prepare the compounds of formula (I). In some instances they may be conveniently added following cleavage. In those cases where the substituents are present on the reagents, care must be taken in the selection of the resin to insure that the substituents are compatible with the selected resin.

[0041] One method for producing the compounds of formula (i) involves synthesis, on resin, of three intermediates, followed by cleavage of the resin to yield the desired product, as outlined in Scheme 1.

[0042] The solid support resin, herein represented by the symbol

[0043] is typically polystyrene, and is terminated with a reactive functional group. There are a number of commercially available resins, with a variety of terminating groups. Suitable examples of support resins for preparation of compounds of formula (I) include: Wang resin (Wang, S. S., J. Am. Chem. Soc., 95,1328 (1973); Kiselov, A. S. and Amstrong, R. W., Tetrahedron Letter, 318, 6163 (1997)), [wherein the terminating group is -(p-phenyl)-CH₂—O-(p-phenyl)-CH₂—OH]; RAPP Tentagel SAM resin (Rotte, B., et. al., Collect. Czech. Chem. Commun., 61, 5304 (1996)), [wherein the terminating group is -(p-phenyl)-CH₂—O-(p-phenyl)-CH₂—NH₂]; vinylsulfonyl resin (Kroll, F. E., et. al., Tetrahedron Lett., 38, 8573, 1997), [wherein the terminating group is -(p-phenyl)-CH₂—SO₂—CH═CH₂]; rink amide resin (Rink, H., Tetrahedron Lett., 28, 3787,1987; Brown, E. G. and Nuss, J. M., Tetrahedron Lett., 38, 8457, 1997), [wherein the terminating group is —CH₂—O-(p-phenyl)-CH₂(NH-Fmoc)-(2,4-dimethoxyphenyl)]; FMPB resin (4-(4-formyl-3-methoxyphenoxy)butyryl AM resin) (Bilodeau, M. T. & Cunningham, A. M., J. Org. Chem., 63, 2800,1998; Kearny, P. T., et. al., J. Org. Chem., 63, 196, 1998) [wherein the terminating group is an aldehyde]; and the like. The appropriate selection of solid support resin and terminating group is based on the synthesis steps, reaction conditions and final compound substituents; and may be determined by one skilled in the art.

[0044] The selected resin and appropriate reactants are employed to prepare resin bound, substituted diamines of formula (II):

[0045] Broadly, there are three approaches described herein to obtain the resin bound substituted diamines of formula (II). In the first approach a commercial resin capable of direct coupling reactions to an appropriately substituted diamine is purchased and reacted to produce the compound of formula (II). In the second approach, a commercial resin is suitably activated to react with an appropriately substituted diamine. This approach is advantageously employed in those cases where the purchased resin is not amine terminated. In the third approach, a commercially available amine terminated resin is reacted with a substituted and protected amine alcohol to form the resin substituted diamine of formula (II). In this third approach, the terminal amine of the selected resin is incorporated into the end product compound.

[0046] Specifically, compounds of formula (II) wherein R² and R³ are hydrogen; wherein R² and R³ are taken together as —C₂-C₃alkyl and R⁴ is other than C(O)—CH₂-phenyl-CH₂— or C(O)—C₁-C₆alkyl-; and wherein R², R³ and R⁴ are taken together with the two N atoms of the diamine portion of the molecule to form

[0047] may be prepared as outlined in Scheme 2 below:

[0048] According to Scheme 2, a commercially available, OH terminated resin is coupled with 4-nitrophenyl chloroformate, in an organic solvent such as DCM, DCE, and the like, preferably DCM, in the presence of an amine base, such as pyridine, N-methylmorpholine (NMM), triethylamine (TEA), diisopropylethylamine (DIEA), and the like, preferably N-methylmorpholine (NMM), preferably at room temperature, to incorporate the —C(O)—O-(p-nitrophenyl)-group into the resin, to form the corresponding p-nitrophenol carbonate terminated resin.

[0049] The p-nitrophenol group on the p-nitrophenol carbonate terminated resin is next displaced with a suitably substituted linear diamine of formula (V), a suitably substituted cyclic diamine of formula (VI), or a suitably substituted bicyclic heterocyclyl diamine of formula (VII), in an organic solvent such as DMF, DMAC, DCM, DCE, and the like, preferably at room temperature, to form the corresponding resin bound substituted diamine of formula (IIa), (IIb) or (IIc), respectively.

[0050] Alternately, compounds of formula (II), wherein R² and R³ are hydrogen may be prepared according to the process outlined in Scheme 3.

[0051] Accordingly, a commercially available, vinylsulfonyl terminated resin is coupled with a suitably substituted linear diamine of formula (V), in an organic solvent such as DMF, overnight, at room temperature, to produce the resin bound substituted diamine of formula (lid). In this approach, the amine group is coupled directly to the terminal methylene group of the vinylsulfonyl terminated resin.

[0052] Compounds of formula (II) wherein R³ is hydrogen and R⁴ is selected from C(O)—CH₂-phenyl-CH₂— or C(O)—C₁-C₆alkyl- may be prepared according to the process outlined in Scheme 4.

[0053] When R² is other than hydrogen, a commercially available amine terminated resin is reacted with a suitably substituted aldehyde of formula (VIII), in an organic solvent such as DCM, DCE, and the like, in the presence of a catalyst such as sodium cyanoborohydride, sodium triacetoxyborohydride and the like, preferably sodium triacetoxyborohydride, preferably at room temperature, to produce the corresponding substituted amine terminated resin of formula (IX).

[0054] The substituted amine terminated resin of formula (IX) is coupled with a suitably substituted Fmoc-protected amine alcohol, a compound of formula (X), in an organic solvent such as DMF, DMAC, DCM, and the like, preferably DMF, preferably at room temperature, to produce the corresponding resin bound Fmoc-protected, substituted diamine of formula (XI). The Fmoc protecting group on the resin bound substituted diamine of formula (XI) is then removed using 20% piperidine in DMF, preferably at room temperature, to produce the corresponding resin bound, substituted diamine of formula (lie).

[0055] Compounds of formula (II) wherein R³ is other than hydrogen may be prepared according to the process outlined in Scheme 5.

[0056] A resin bound substituted diamine of formula (lie) is coupled with a suitably substituted aldehyde of formula (XII), in the presence of a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydide, and the like, preferably triacetoxyborohydride, in an organic solvent such as DCM, DCE, and the like, preferably DCE, preferably at room temperature, to produce the corresponding resin bound substituted diamine of formula (II).

[0057] The resin bound, substituted diamines of formula (II) are next reacted with suitably substituted reagents to produce the corresponding resin bound, substituted secondary amine of formula (III):

[0058] In a general approach to producing the resin bound substituted triamine of formula (III), bromoacetic acid is initially coupled to the diamine for formula (II), followed by coupling of a suitably substituted amine.

[0059] More specifically, in this approach, compounds of formula (III) may be prepared according to the process outlined in Scheme 6. This approach is also particularly advantageous in the preparation of compounds of formula (I) wherein L is —C₃-C₆cycloalkyl.

[0060] Accordingly, a resin bound, substituted diamine of formula (II) is coupled with bromoacetic acid, using a coupling agent such as diisopropyl carbodiimide, 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiamide, and the like, preferably diisopropylcarbodiamide, in a solvent such as DMF, DMAC, and the like, preferably DMF, preferably at room temperature, to form the corresponding resin bound, bromoacetylated alkylcarbonyl diamine of formula (XIII).

[0061] The bromine on the resin bound, bromoacetylated alkylcarbonyl diamine of formula (XIII) is then displaced with a suitably substituted amine of formula (XIV), in a solvent such as DMSO, preferably at room temperature, to form the corresponding resin bound, substituted secondary amine of formula (III).

[0062] The resin bound, substituted secondary amine of formula (III) is subsequently reacted with suitably substituted reagents to produce the corresponding resin bound, compound of formula (IV):

[0063] The resin bound compound of formula (IV) may be prepared via two processes. In the first process, the resin bound, substituted secondary amine of formula (III) is directly coupled with a suitably substituted sulfonyl chloride, suitably substituted carbonyl chloride or suitably substituted isocyanate reagent to prepared the end product compound. In the second process, the resin bound, substituted secondary amine of formula (III) is first coupled with a halogen substituted aryl or heteroaryl sulfonyl chloride, followed by displacement of the halogen with a suitably substituted aryl or heteroaryl substituted boronic acid, to yield the end product compound.

[0064] More particularly, in the first process, the resin bound compound of formula (IV) is prepared as outlined in Scheme 7.

[0065] According to the first process, the resin bound, substituted secondary amine of formula (III) is coupled with a suitably substituted chloride of formula (XV), or a suitably substituted isocyanate of formula (XVI), in a solvent such as DCM, DCE, chloroform, and the like, preferably DCM, in the presence of an amine base such as pyridine, N-methylmorpholine (NMM), triethyl amine (TEA), diisopropylethylamine (DIEA), and the like, preferably pyridine, preferably at room temperature, to form the corresponding resin bound compound of formula (IV).

[0066] The second process is particularly advantageous for preparation of compounds of formula (I) wherein Z is sulfonyl, n is 0, q is 1 and the

[0067] substituent is phenyl, napthyl, thienyl or furyl. The second process is also particularly advantageous for preparation of compounds of formula (I) wherein R² and R³ are taken together as C₂-C₃alkyl and Z is sulfonyl; and wherein R², R³, and R⁴ are taken together with the two N atoms of the diamine portion of the molecule to form

[0068] In the second process, the resin bound compound of formula (IV) is prepared via the process outlined in Scheme 8.

[0069] The resin bound, substituted secondary amine of formula (III) is coupled with a suitably substituted aryl or heteroaryl sulfonyl chloride of formula (XVII), wherein A represents a halogen selected from chlorine, bromine or iodine, preferably bromine, in a solvent such as DCM, DCE, chloroform, and the like, preferably DCM, in the presence of an amine base such as pyridine, N-methylmorpholine, triethylamine (TEA), diisopropylethylamine (DIEA), and the like, preferably pyridine, preferably at room temperature, to form the corresponding resin bound, substituted sulfonyl compound of formula (XVIII).

[0070] On the resin bound, substituted sulfonyl of formula (XVIII), the halogen represented by A is next displaced with a suitably substituted boronic acid of formula (XIX), using Suzuki conditions (in a solvent such as dimethoxyethane (DME), dioxane, and the like, in the presence of a base such as 2M sodium carbonate, tetramethylguanadine (TMG), and the like, under a N₂ atmosphere, at a temperature in the range of about 80-100° C., in the presence of a catalyst, such as palladium tetrakistriphenylphosphine), to form the corresponding resin bound, substituted sulfonamide formula (IVa).

[0071] The resin bound compound of formula (IV), may next be treated to yield the corresponding compound of formula (I) by cleaving the solid support resin, using a cleaving cocktail, such as 90:10 TFA:water, preferably at room temperature, to produce the corresponding compound of formula (I).

[0072] A resin bound compound of formula (IVa) may alternatively be further reacted with a suitably substituted compound of formula (XX) and/or formula (XXI), wherein J is bromine or iodine, to incorporate R¹ and R² substituents, wherein R¹═R² and are other than hydrogen. For this process, the preferred resin is the vinylsulfonyl terminated resin, R⁴ is other than —C(O)—CH₂-phenyl- or —C(O)—C₁-C₆alkyl-, and the R¹ and R² substituents are incorporated according to the process outlined in Scheme 9.

[0073] Accordingly, a resin bound compound of formula (IVa) is reacted with a suitably substituted compound of formula (XX) and/or formula (XXI), wherein J is bromine or iodine, preferably at room temperature, to produce the corresponding resin bound, quaternary amine of formula (XXil).

[0074] The resin bound quaternary amine of formula (XXVI) is then treated to yield the desired corresponding compound of formula (I) by cleaving the solid support resin, using a cleaving cocktail, such as 20% DIEA in DMF, preferably at room temperature, to produce the corresponding compound of formula (I).

[0075] In an alternative scheme for producing compounds of formula (I) wherein R¹ and/or R² are other than hydrogen, the R¹ and R² substituents may be introduced following cleavage of the resin bound compound of formula (IV). More particularly, such a process is as outlined in Scheme 10.

[0076] A compound of formula (Ia), wherein R¹ and R² are hydrogen, is treated with a suitably substituted aldehyde of formula (XXIII), preferably in the amount of at least one molar equivalent, in an organic solvent such as TMOF, and the like, in the presence of a reducing agent such as sodium triacetoxyborohydride, and the like, preferably at room temperature, and then with a suitably substituted aldehyde of formula (XXIV), preferably in the amount of at least one molar equivalent, in an organic solvent such as TMOF, and the like, in the presence of a reducing agent such as sodium triacetoxyborohydride, and the like, preferably at room temperature, to produce the corresponding compound of formula (I).

[0077] In an alternative method of Scheme 10, compounds of formula (I), wherein R¹ and R² are the same and other than hydrogen, are produced by treating the compound of formula (Ia) with at least two molar equivalents of a suitably substituted aldehyde of formula (XXIII) or (XXIV), to produce the corresponding product of formula (I).

[0078] In another alternative method of Scheme 10, compounds of formula (I), wherein one of R¹ or R² is hydrogen, the compound of formula (Ia) is treated with at least one molar equivalent of a suitably substituted aldehyde of formula (XXIII) or (XXIV), to yield the desired corresponding compound of formula (I).

[0079] Compounds of formula (I), wherein R¹ and/or R² is alkylcarbonyl may be prepared according to the process outlined in Scheme 11.

[0080] Accordingly, a suitably substituted compound of formula (Ia), wherein R¹ and R² are each hydrogen, is treated with a suitably substituted acid chloride of formula (XXV), preferably in the amount of at least one molar equivalent, in an organic solvent such as chloroform, DCM, and the like, in the presence of a organic base such as TEA, and the like, preferably at room temperature, to yield the corresponding compound of formula (Ib). Alternatively, a suitably substituted compound of formula (Ia), wherein R¹ and R² are each hydrogen, is treated with a suitably substituted carboxylic acid of formula (XXVI), preferably in the amount of at least one molar equivalent, in an organic solvent such as DMF, and the like, in the presence of a coupling agent such as DIC, and the like, preferably at room temperature, to yield the corresponding compound of formula (Ib).

[0081] As used herein, unless otherwise noted, “alkyl” whether used alone or as part of a substituent group, shall include straight and branched chains containing 1 to 6 carbon atoms. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 2-methyl-3-butyl, hexyl and the like. Similarly, the term “cycloalkyl” shall include saturated alkyl ring structures containing 3 to 6 carbon atoms. Suitable examples include cyclopropyl, cyclobutyl, cyclopentyl and cylcohexyl.

[0082] As used herein, unless otherwise noted, “alkenyl” and “alkynyl” shall include straight and branched chain alkene and alkyne having 1 to 6 carbon atoms, for example allyl, vinyl, 2-propenyl, 2-propynyl, and the like.

[0083] As used herein, unless otherwise noted, “alkoxy” shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, propoxy, sec-butoxy, t-butoxy, 2-methyl-3-bytoxy and the like.

[0084] As used herein the terms “aromatic and aryl” shall denote phenyl and naphthyl.

[0085] Suitable “six membered heteroaryis containing one to three nitrogen atoms” include pyridyl, pyridizanyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl and 1,2,3-triazinyl.

[0086] Suitable “five membered heteroaryl containing one sulfur, oxygen or nitrogen atom, optionally containing one to three additional nitrogen atoms” include thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and the like.

[0087] As used herein, unless otherwise noted, “halogen” shall denote chlorine, bromine, fluorine and iodine.

[0088] As used herein, unless otherwise noted, “*” represents the presence of a stereogenic center.

[0089] Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a “phenylC₁-C₆alkylamidoC₁-C₆alkyl” substituent refers to a group of the formula

[0090] In a preferred embodiment of the present invention are compounds of the formula (I) wherein

[0091] R¹ and R² are independently selected from the group consisting of hydrogen, methyl, ethyl, methylcarbonyl, trifluoromethyl, phenyl, benzyl, phenylcarbonyl, pyridyl, pyridylcarbonyl, thienyl, thienylmethyl and thienylcarbonyl (where the phenyl, pyridyl or thienyl is optionally substituted with one to two substituents independently selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, trifluoromethyl, trifluoromethoxy or nitro); and

[0092] R³ is selected from the group consisting of hydrogen, methyl, —CH═CH— (optionally substituted with phenyl, pyridyl or thienyl; wherein the phenyl, pyridyl or thienyl is further optionally substituted with one to two substituents independently selected from the group consisting of halogen, C₁-C₃alkyl, C₁-C₃alkoxy, trifluoromethyl, trifluoromethoxy and nitro), —C≡C—, (optionally substituted with phenyl, pyridyl or thienyl; wherein the phenyl, pyridyl or thienyl is further optionally substituted with one to two substituents independently selected from the group consisting of halogen, C₁-C₃alkyl, C₁-C₃alkoxy, trifluoromethyl, trifluoromethoxy and nitro).

[0093] More preferably, R¹, R², and R³ are the same; most preferably R¹, R² and R³ are the same and are hydrogen.

[0094] In another preferred embodiment of the present invention are compounds of the formula (I) wherein R² and R³ are taken together as C₂-C₃alkyl, more preferably 1,2-ethyl; and R⁴ is C₂-C₆alkyl, more preferably 1,2-ethyl or 1,3-n-propyl.

[0095] In another preferred embodiment of the present invention are compounds of the formula (I) wherein R², R³, and R⁴ are taken together with the two N atoms of the diamine portion of the molecule to form

[0096] Preferred R⁴ substituents include —C₂-C₆alkyl, -cyclohexyl, —CH₂-cyclohexyl-CH₂, -cyclohexyl-CH₂-cyclohexyl and —CH₂-phenyl-CH₂.

[0097] In another preferred embodiment of the invention are compounds of the formula (I) wherein R², R³, and R⁴ may be taken together with the two N atoms of the diamine portion of the molecule to form 4,4′-bipiperidinyl.

[0098] Preferred L substituents include -cyclopropyl-, cyclohexyl-, (wherein the cylcopropyl or cyclohexyl is substituted with R⁵ and R⁶),

[0099] Preferred R⁵ substituents include phenyl (wherein the phenyl is optionally substituted with one to two substituents independently selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, trifluoromethyl, trifluoromethoxy, methylcarbonylamino, methylsulfonylamino, nitro, acetomido, amino, C₁-C₃alkylamino or di(C₁-C₃alkyl)amino), N-methylpyrrolidinyl, 3,4-methylenedioxyphenyl, bicyclo[4.2.0]octa-1,3,5-trienyl, 2,3-dihydro-1H-indolyl, C₃-C₆cycloalkenyl (wherein the cycloalkenyl contains one or two double bonds), thienyl, furyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyrazinyl and triazinyl.

[0100] Preferred R⁶ substituents include hydrogen, C₁-C₃alkyl, cyclopropyl, cyclobutyl, cyclohexyl, C₁-C₃alkoxy, hydroxy and phenyl (wherein the phenyl is optionally substituted with one to two substituents independently selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, trifluoromethyl or trifluoromethoxy); provided that R⁶ is phenyl only when R⁵ is phenyl.

[0101] Preferred R⁸ substituents include hydrogen and C₁-C₃alkyl.

[0102] Preferably Z is selected from the group consisting of SO₂, C(═O) and —C(═O)—NH—.

[0103] Preferred

[0104] substituents include phenyl, naphthyl, quinolinyl and thienyl.

[0105] Preferably n is 0 to 2.

[0106] Preferred X substituents include halogen, C₁-C₆alkyl, C₁-C₄alkoxy, trifluoromethyl, trifluoromethoxy, nitro, acetamido, amino, C₁-C₃alkylamino and di(C₁-C₃alkyl)amino.

[0107] Preferred Y substituents include phenyl, naphthyl, (wherein the phenyl or naphthyl is optionally substituted with one to three substituents independently selected from halogen, C₀-C₃alkyl, C₁-C₃alkoxy, trifluoromethyl, trifluoromethoxy, formyl, nitro, cyano, methylthio, acetamido, amino, aminocarbonyl, C₁-C₃alkylamino, di(C₁-C₃alkyl)amino, carboxy, —COO(C₁-C₃alkyl), COO(C₁-C₃alkylphenyl), C₁₋₄alkylaminosulfonyl, C₁-C₄alkylcarbonylamino), biphenyl, 3,4-methylenedioxyphenyl, dianthryl, dibenzothienyl, phenoxathiinyl, a five membered heteroaryl (wherein the five membered heteroaryl contains one nitrogen, oxygen or sulfur atom and optionally contains an additional nitrogen or oxygen atom) and a six membered heteroaryl (wherein the six membered heteroaryl contains one nitrogen atom and optionally contains an additional nitrogen or oxygen atom); wherein the five or six membered heteroaryl is optionally substituted with one to two substituents independently selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, trifluoromethyl, trifluoromethoxy, formyl, nitro, cyano, methylthio, acetamido, amino, aminocarbonyl, C₁-C₃alkylamino or di(C₁-C₃alkyl)amino; and wherein the point of attachment for the five or six membered heteroaryl is a carbon atom.

[0108] Particularly preferred compounds of the present invention are listed in Table 1, below. TABLE 1

Cmpd # m R⁵ R⁶ Stereo p Y 336 1 2-methoxyphenyl H — 0 2-methylphenyl 337 1 2-methoxyphenyl H — 0 2-chlorophenyl 338 1 2-methoxyphenyl H — 0 2-methoxyphenyl 339 1 2-methoxyphenyl H — 0 2,4-dichlorophenyl 340 0 2-methoxyphenyl H — 0 2-methylphenyl 341 0 2-methoxyphenyl H — 0 2-chlorophenyl 342 0 2-methoxyphenyl H — 0 2-methoxyphenyl 343 0 2-methoxyphenyl H — 0 2,4-dichlorophenyl 384 1 phenyl CH₃ R 0 2-methylphenyl 385 1 phenyl CH₃ R 0 2-chlorophenyl 386 1 phenyl CH₃ R 0 3-fluorophenyl 387 1 phenyl CH₃ S 0 2-methylphenyl 388 1 phenyl CH₃ S 0 2-chlorophenyl 389 1 phenyl CH₃ S 0 3-fluorophenyl

Cmpd # m R⁵ R⁶ Stereo p Y 344 1 2-methoxyphenyl H — 0 2-methylphenyl 345 1 2-methoxyphenyl H — 0 2-chlorophenyl 346 1 2-methoxyphenyl H — 0 2-methoxyphenyl 347 1 2-methoxyphenyl H — 0 2,4-dichlorophenyl 348 0 2-methoxyphenyl H — 0 2-methyl 349 0 2-methoxyphenyl H — 0 2-chlorophenyl 350 0 2-methoxyphenyl H — 0 2-methoxyphenyl 351 0 2-methoxyphenyl H — 0 2,4-dichlorophenyl 390 1 phenyl CH₃ R 0 2-methylphenyl 391 1 phenyl CH₃ R 0 2-chlorophenyl 392 1 phenyl CH₃ R 0 3-fluorophenyl 393 1 phenyl CH₃ S 0 2-methylphenyl 394 1 phenyl CH₃ S 0 2-chlorophenyl 395 1 phenyl CH₃ S 0 3-fluorophenyl

Cmpd # m Y 74 0 2-methylphenyl 75 0 3-thienyl 76 0 2-methoxyphenyl 77 0 4-fluorophenyl 78 0 2,3-dimethoxyphenyl 79 0 4-methoxyphenyl 80 0 4-methylphenyl 81 0 1-naphthyl 82 0 2-chlorophenyl 83 0 3-pyridyl 84 0 2-thienyl 85 0 3-aminocarbonylphenyl 86 0 phenyl 87 0 4-chlorophenyl 88 0 4-[3,5-dimethylisoxazolyl] 89 0 2-furyl 90 0 4-cyanophenyl 91 0 4-pyridyl 92 0 3-methoxyphenyl 93 0 4-aminophenyl 94 1 2-methylphenyl 95 1 3-thienyl 96 1 2-methoxyphenyl 97 1 4-fluorophenyl 98 1 2,3-dimethoxyphenyl 99 1 4-methoxyphenyl 100 1 4-methylphenyl 101 1 1-naphthyl 102 1 2-chlorophenyl 103 1 3-pyridyl 104 1 2-thienyl 105 1 3-aminocarbonylphenyl 106 1 phenyl 107 1 4-chlorophenyl 108 1 4-[3,4-dimethylisoxazolyl] 109 1 2-furyl 110 1 4-cyano phenyl 111 1 4-pyridyl 112 1 3-methoxyphenyl 113 1 4-aminophenyl

Cmpd # m R⁵ R⁶ Y 1 0 2-methoxyphenyl H 4-chlorophenyl 2 0 2-methoxyphenyl H 3-trifluoromethylphenyl 3 0 2-methoxyphenyl H 2-chloophenyl 4 0 2-methoxyphenyl H 2-methylphenyl 5 0 2-methoxyphenyl H 2-methoxyphenyl 6 0 2-methoxyphenyl H 2,4-dichlorophenyl 7 0 2-methoxyphenyl H 3,5-di(trifluoromethyl) phenyl 8 0 2-methoxyphenyl H 3-chloro-4-fluorophenyl 9 0 2-methoxyphenyl H 4-methoxyphenyl 20 0 3-methoxyphenyl H 3-trifluoromethylphenyl 21 0 3-methoxyphenyl H 2-methoxyphenyl 22 0 3-methoxyphenyl H 2,4-dichlorophenyl 23 0 3-methoxyphenyl H 3-fluorophenyl 24 0 3-methoxyphenyl H 3-methoxyphenyl 25 0 3-methoxyphenyl H 4-methylphenyl 26 0 3-methoxyphenyl H 4-fluorophenyl 27 0 3-methoxyphenyl H 3-chloro-4-fluorophenyl 28 0 3-methoxyphenyl H 4-methoxyphenyl 29 1 2-methoxyphenyl H 3-trifluoromethyl phenyl 30 1 2-methoxyphenyl H 3-nitrophenyl 31 1 2-methoxyphenyl H 2-chlorophenyl 32 1 2-methoxyphenyl H 2-methylphenyl 33 1 2-methoxyphenyl H 2-methoxyphenyl 34 1 2-methoxyphenyl H 2,4-dichlorophenyl 35 1 2-methoxyphenyl H phenyl 36 1 2-methoxyphenyl H 4-fluorophenyl 37 1 2-methoxyphenyl H 3-chlorophenyl 38 1 2-methoxyphenyl H 2-trifluoromethyl phenyl

Cmpd # R⁵ R⁶ p

X 39 2-methoxyphenyl H 0 phenyl — 40 2-methoxyphenyl H 0 2-thienyl 5-chloro 41 2-methoxyphenyl H 0 1-phenyl 3-trifluoromethyl 42 2-methoxyphenyl H 0 1-phenyl 2-trifluoromethyl 43 2-methoxyphenyl H 0 1-phenyl 3-chloro 44 2-methoxyphenyl H 0 1-phenyl 3,4-dichloro 45 2-methoxyphenyl H 0 2-naphthyl — 46 2-methoxyphenyl H 0 1-phenyl 2-chloro 47 2-methoxyphenyl H 0 1-phenyl 4-chloo 48 2-methoxyphenyl H 0 3-thienyl 2,5-dichloro 49 2-methoxyphenyl H 0 1-phenyl 2,4-dichloro 50 2-methoxyphenyl H 0 1-phenyl 2,6-dichloro 51 2-methoxyphenyl H 0 1-phenyl 3,5-dichloro 52 2-methoxyphenyl H 0 1-phenyl 2,5-dichloro 53 2-methoxyphenyl H 0 1-phenyl 2,3-dichloro 54 2-methoxyphenyl H 1 phenyl — 55 2-methoxyphenyl H 0 1-phenyl 4-methyl 56 2-methoxyphenyl H 0 1-phenyl 4-methoxy 57 2-methoxyphenyl H 0 1-naphthyl — 58 2-methoxyphenyl H 0 1-phenyl 4-fluoro 59 2-methoxyphenyl H 0 1-phenyl 3,4-dimethoxy 60 2-methoxyphenyl H 0 1-phenyl 2,5-dimethoxy 61 2-methoxyphenyl H 0 1-phenyl 2-nitro 62 2-methoxyphenyl H 0 1-phenyl 4-nitro 63 2-methoxyphenyl H 0 1-phenyl 3-nitro 64 2-methoxyphenyl H 0 1-phenyl 4-iodo 65 2-methoxyphenyl H 0 1-phenyl 4-tert-butyl 66 2-methoxyphenyl H 0 1-phenyl 2-nitro-4-methoxy 67 2-methoxyphenyl H 0 1-phenyl 3-methyl-4-methoxy 68 2-methoxyphenyl H 0 1-phenyl 2-nitro-4- trifluoromethyl 69 2-methoxyphenyl H 0 1-phenyl 3-fluoro 70 2-methoxyphenyl H 0 1-phenyl 2-fluoro 71 2-methoxyphenyl H 0 1-phenyl 4-trifluoromethyl 72 2-methoxyphenyl H 0 1-phenyl 4-trifluoromethoxy 402 2-methoxyphenyl H 0 1-phenyl 2,3-dichloro 403 3,4-methylene H 0 8-quinolinyl — dioxyphenyl

Cmpd # Stereo Y 372 R 2-methylphenyl 373 R 2-chlorophenyl 374 R 3-fluorophenyl 375 S 2-methylphenyl 376 S 2-chlorophenyl 377 S 3-fluorophenyl

Cmpd # R⁵ R⁶ Stereo

Y 10 2-methoxyphenyl H — 1,4-phenyl 3-nitrophenyl 11 2-methoxyphenyl H — 1,4-phenyl 2-chlorophenyl 12 2-methoxyphenyl H — 1,4-phenyl 2-methylphenyl 13 2-methoxyphenyl H — 1,4-phenyl 2-methoxy phenyl 14 2-methoxyphenyl H — 1,4-phenyl 3-fluorophenyl 15 2-methoxyphenyl H — 1,4-phenyl phenyl 16 2-methoxyphenyl H — 1,4-phenyl 3-methoxy phenyl 17 2-methoxyphenyl H — 1,4-phenyl 4-fluorophenyl 18 2-methoxyphenyl H — 1,4-phenyl 2-trifluoro methylphenyl 19 2-methoxyphenyl H — 1,4-phenyl 3-chloro-4- fluorophenyl 197 phenyl H R 1,4-phenyl phenyl 207 phenyl H S 1,4-phenyl phenyl 208 phenyl H S 1,4-phenyl 2-chlorophenyl 209 phenyl H S 1,4-phenyl 3-chlorophenyl 210 phenyl H S 1,4-phenyl 2-methoxyphenyl 211 phenyl H S 1,4-phenyl 3-methoxyphenyl 212 phenyl H S 1,4-phenyl 4-methoxyphenyl 213 phenyl H S 1,4-phenyl 3-fluorophenyl 214 phenyl H S 1,4-phenyl 4-fluorophenyl 215 phenyl H S 1,4-phenyl 2-methylphenyl 216 phenyl H S 1,4-phenyl 4-methylphenyl 217 2-methoxyphenyl H — 1,2-phenyl 2-thienyl 218 2-methoxyphenyl H — 1,2-phenyl 2-methylphenyl 219 2-methoxyphenyl H — 1,2-phenyl 3-thienyl 220 2-methoxyphenyl H — 1,2-phenyl 2-methoxyphenyl 221 2-methoxyphenyl H — 1,2-phenyl 4-fluorophenyl 222 2-methoxyphenyl H — 1,2-phenyl 4-methoxyphenyl 223 2-methoxyphenyl H — 1,2-phenyl 4-methylphenyl 224 2-methoxyphenyl H — 1,2-phenyl 1-naphthyl 225 2-methoxyphenyl H — 1,2-phenyl 4-chlorophenyl 226 2-methoxyphenyl H — 1,2-phenyl 3-methoxy phenyl 227 2-methoxyphenyl H — 1,2-phenyl 3-aminophenyl 228 2-methoxyphenyl H — 1,2-phenyl 3-fluorophenyl 229 2-methoxyphenyl H — 1,2-phenyl 2-fluorophenyl 230 2-methoxyphenyl H — 1,2-phenyl 1-(3,4-methylene dioxyphenyl) 232 2-methoxyphenyl H — 1,2-phenyl phenyl 233 2-methoxyphenyl H — 1,2-phenyl 4-(3,5-dimethyl isoxazole) 234 2-methoxyphenyl H — 1,2-phenyl 4-cyanophenyl 235 2-methoxyphenyl H — 1,2-phenyl 4-pyridyl 236 2-methoxyphenyl H — 1,2-phenyl 2,3,4- trimethoxyphenyl 237 2-methoxyphenyl H — 1,2-phenyl 3-cyanophenyl 238 2-methoxyphenyl H — 1,2-phenyl 2,5-dimethoxy phenyl 239 2-methoxyphenyl H — 1,2-phenyl 2,4-dichloro phenyl 240 2-methoxyphenyl H — 1,2-phenyl 3-trifluoro methylphenyl 241 2-methoxyphenyl H — 1,2-phenyl 4-trifluoro methylphenyl 242 2-methoxyphenyl H — 1,2-phenyl 2-trifluoro methylphenyl 243 2-methoxyphenyl H — 1,2-phenyl 3-methylphenyl 244 2-methoxyphenyl H — 1,3-phenyl 2-methylphenyl 245 2-methoxyphenyl H — 1,3-phenyl 3-thienyl 246 2-methoxyphenyl H — 1,3-phenyl 2-methoxyphenyl 247 2-methoxyphenyl H — 1,3-phenyl 4-fluorophenyl 248 2-methoxyphenyl H — 1,3-phenyl 4-methoxyphenyl 249 2-methoxyphenyl H — 1,3-phenyl 4-methoxyphenyl 250 2-methoxyphenyl H — 1,3-phenyl 1-naphthyl 251 2-methoxyphenyl H — 1,3-phenyl 3-pyridyl 253 2-methoxyphenyl H — 1,3-phenyl 4-chlorophenyl 254 2-methoxyphenyl H — 1,3-phenyl 3-methoxyphenyl 255 2-methoxyphenyl H — 1,3-phenyl 3-aminophenyl 256 2-methoxyphenyl H — 1,3-phenyl 3-fluorophenyl 257 2-methoxyphenyl H — 1,3-phenyl 2-fluorophenyl 258 2-methoxyphenyl H — 1,3-phenyl 1-(3,4-methylene dioxyphenyl) 259 2-methoxyphenyl H — 1,3-phenyl 3-chlorophenyl 260 2-methoxyphenyl H — 1,3-phenyl phenyl 261 2-methoxyphenyl H — 1,3-phenyl 4-(3,5-dimethyl isoxazole) 262 2-methoxyphenyl H — 1,3-phenyl 4-cyanophenyl 263 2-methoxyphenyl H — 1,3-phenyl 4-pyridyl 264 2-methoxyphenyl H — 1,3-phenyl 2,3,4- trimethoxyphenyl 265 2-methoxyphenyl H — 1,3-phenyl 4-cyanophenyl 266 2-methoxyphenyl H — 1,3-phenyl 2,5-dimethoxy phenyl 267 2-methoxyphenyl H — 1,3-phenyl 3-trifluoro methylphenyl 268 2-methoxyphenyl H — 1,3-phenyl 4-trifluoro methylphenyl 269 2-methoxyphenyl H — 1,3-phenyl 2-trifluoro methylphenyl 270 2-methoxyphenyl H — 1,3-phenyl 3-methylphenyl 271 2-methoxyphenyl H — 2,5-thienyl 2-thienyl 272 2-methoxyphenyl H — 2,5-thienyl 2-methylphenyl 273 2-methoxyphenyl H — 2,5-thienyl 3-thienyl 274 2-methoxyphenyl H — 2,5-thienyl 2-methoxyphenyl 275 2-methoxyphenyl H — 2,5-thienyl 4-fluorophenyl 276 2-methoxyphenyl H — 2,5-thienyl 4-methoxyphenyl 277 2-methoxyphenyl H — 2,5-thienyl 4-methylphenyl 279 2-methoxyphenyl H — 2,5-thienyl 2-chlorophenyl 280 2-methoxyphenyl H — 2,5-thienyl 3-pyridyl 281 2-methoxyphenyl H — 2,5-thienyl 4-chlorophenyl 282 2-methoxyphenyl H — 2,5-thienyl 3-methoxyphenyl 283 2-methoxyphenyl H — 2,5-thienyl 3-aminophenyl 284 2-methoxyphenyl H — 2,5-thienyl 3-fluorophenyl 285 2-methoxyphenyl H — 2,5-thienyl 2-fluorophenyl 287 2-methoxyphenyl H — 2,5-thienyl 3-chlorophenyl 288 2-methoxyphenyl H — 2,5-thienyl phenyl 289 2-methoxyphenyl H — 2,5-thienyl 4-(3,5-dimethyl isoxazole) 290 2-methoxyphenyl H — 2,5-thienyl 4-cyanophenyl 291 2-methoxyphenyl H — 2,5-thienyl 4-pyridyl 292 2-methoxyphenyl H — 2,5-thienyl 2,3,4- trimethoxyphenyl 293 2-methoxyphenyl H — 2,5-thienyl 3-cyanophenyl 294 2-methoxyphenyl H — 2,5-thienyl 2-furyl 295 2-methoxyphenyl H — 2,5-thienyl 2,5-dimethoxy phenyl 296 2-methoxyphenyl H — 2,5-thienyl 2,4-dichloro phenyl 297 2-methoxyphenyl H — 2,5-thienyl 3-trifluoro methylphenyl 298 2-methoxyphenyl H — 2,5-thienyl 4-trifluoro methylphenyl 299 2-methoxyphenyl H — 2,5-thienyl 2-trifluoro methylphenyl 300 2-methoxyphenyl H — 2,5-thienyl 3-methylphenyl

Cmpd # p m

X 114 0 1 2-thienyl 5-chloro 115 0 1 phenyl 3-trifluoromethyl 116 0 1 phenyl 2-trifluoromethyl 117 0 1 phenyl 3-chloro 118 0 1 phenyl 3,4-dichloro 119 0 1 2-naphthyl — 120 0 1 phenyl 2-chloo 121 0 1 phenyl 2,5-dimethoxy 122 0 1 phenyl 2,4-dichloro 123 0 1 phenyl 2,6-dichloro 124 0 1 phenyl 2,5-dichloro 125 0 1 phenyl 3,5-dichloro 126 0 1 2-thienyl 4,5-dichloro 127 1 1 phenyl — 128 0 1 phenyl 4-methoxy 129 0 1 1-naphthyl — 130 0 1 phenyl 4-fluoro 131 0 1 phenyl 3-fluoro 132 0 1 phenyl 2-fluoro 133 0 1 phenyl 3,4-dimethoxy 134 0 1 phenyl 2-nitro 135 0 1 phenyl 3-nitro 136 0 1 phenyl 4-nitro 137 0 1 phenyl 4-iodo 138 0 1 phenyl 4-t-butyl 139 0 1 phenyl 2-nitro-4-methoxy 140 0 1 phenyl 2-methoxy-5-methyl 141 0 1 2-thienyl 4-nitro-5-chloro 142 0 1 phenyl 2-nitro-4-trifluoro methyl 143 0 1 phenyl 4-trifluoromethyl 144 0 1 phenyl 4-trifluoromethoxy 147 0 1 2-thienyl — 148 0 1 phenyl 4-methyl 149 0 1 phenyl 4-chloro 150 0 1 phenyl — 404 0 0 1-phenyl 2,3-dichloro

Cmpd # R⁵

Y 73 2-methoxyphenyl 2-thienyl 5-(2-methylthio-pyrimidyl) 405 3,4-methylene 8-quinolinyl — dioxyphenyl

Ster- Cmpd # R⁵ R⁶ eo Z

Y 145 2-methoxy H — SO₂ 2,5-thienyl 2-pyridyl phenyl 146 2-methoxy H — SO₂ 2,5-thienyl 5-(2-methylthio- phenyl pyrimidyl) 198 phenyl CH₃ R SO₂ 1,4-phenyl 2-chlorophenyl 199 phenyl CH₃ R SO₂ 1,4-phenyl 3-chlorophenyl 200 phenyl CH₃ R SO₂ 1,4-phenyl 2-methoxyphenyl 201 phenyl CH₃ R SO₂ 1,4-phenyl 3-methoxyphenyl 202 phenyl CH₃ R SO₂ 1,4-phenyl 4-methoxyphenyl 203 phenyl CH₃ R SO₂ 1,4-phenyl 3-fluorophenyl 204 phenyl CH₃ R SO₂ 1,4-phenyl 4-fluorophenyl 205 phenyl CH₃ R SO₂ 1,4-phenyl 2-methylphenyl 206 phenyl CH₃ R SO₂ 1,4-phenyl 4-methylphenyl 231 2-methoxy H — SO₂ 1,2-phenyl 3-chlorophenyl phenyl 251 2-methoxy H — SO₂ 1,3-phenyl 2-chlorophenyl phenyl 278 2-methoxy H — SO₂ 2,5-thienyl 1-naphthyl phenyl 286 2-methoxy H — SO₂ 2,5-thienyl 1-(3,4-methylene phenyl dioxyphenyl) 301 phenyl CH₃ R SO₂ 1,4-phenyl 2-fluorophenyl 302 phenyl CH₃ R SO₂ 1,4-phenyl 2,6-dichlorophenyl 303 phenyl CH₃ R SO₂ 1,4-phenyl 2,4-dichlorophenyl 304 phenyl CH₃ R SO₂ 1,4-phenyl 2-trifluoromethyl phenyl 305 phenyl CH₃ R SO₂ 1,4-phenyl 2,4,6-trimethyl phenyl 306 phenyl CH₃ S SO₂ 1,4-phenyl 2-fluorophenyl 307 phenyl CH₃ S SO₂ 1,4-phenyl 2,6-difluorophenyl 308 phenyl CH₃ S SO₂ 1,4-phenyl 2,4-dichlorophenyl 309 phenyl CH₃ S SO₂ 1,4-phenyl 2-trifluoromethyl phenyl 310 phenyl CH₃ S SO₂ 1,4-phenyl 2,4,6- trimethylphenyl 311 phenyl CH₃ Mix SO₂ 1,4-phenyl 2-methylphenyl 312 phenyl CH₃ Mix SO₂ 1,4-phenyl 2-chlorophenyl 313 phenyl CH₃ Mix SO₂ 1,4-phenyl 3-fluorophenyl 314 4-chloro CH₃ Mix SO₂ 1,4-phenyl 2-methylphenyl phenyl 315 4-chloro CH₃ Mix SO₂ 1,4-phenyl 2-chlorophenyl phenyl 316 4-chloro CH₃ Mix SO₂ 1,4-phenyl 3-fluorophenyl phenyl 317 4-chloro cyclo- — SO₂ 1,4-phenyl 2-methylphenyl phenyl propyl 318 4-chloro cyclo- — SO₂ 1,4-phenyl 2-chlorophenyl phenyl propyl 319 4-chloro cyclo- — SO₂ 1,4-phenyl 3-fluorophenyl phenyl propyl 323 phenyl H — SO₂ 1,4-phenyl 2-methylphenyl 324 phenyl H — SO₂ 1,4-phenyl 2-chlorophenyl 325 phenyl H — SO₂ 1,4-phenyl 3-fluorophenyl 412 phenyl CH₃ R SO₂ 1,4-phenyl phenyl 413 phenyl CH₃ R SO₂ 1,4-phenyl 3-nitrophenyl 414 phenyl CH₃ R SO₂ 1,4-phenyl 4-fluorophenyl 415 phenyl CH₃ R SO₂ 1,4-phenyl 2-methylphenyl 416 phenyl CH₃ R SO₂ 1,4-phenyl 3-trifluoromethyl phenyl 417 phenyl CH₃ R SO₂ 1,4-phenyl 4-trifluoromethyl phenyl 418 phenyl CH₃ R SO₂ 1,4-phenyl 3-chlorophenyl 419 phenyl CH₃ R SO₂ 1,4-phenyl 3-methoxy phenyl 420 phenyl CH₃ R SO₂ 1,4-phenyl 2-trifluoromethyl phenyl 421 phenyl CH₃ R SO₂ 1,4-phenyl 2-methoxy phenyl 422 phenyl CH₃ R SO₂ 1,4-phenyl 4-trifluoro methoxyphenyl 423 phenyl CH₃ R SO₂ 1,4-phenyl 3-fluorophenyl 424 phenyl CH₃ R SO₂ 1,4-phenyl 2-naphthyl 425 phenyl CH₃ R SO₂ 1,4-phenyl 3-chloro-4- fluorophenyl 426 phenyl CH₃ R SO₂ 1,4-phenyl 3-bromophenyl 427 phenyl CH₃ R SO₂ 1,4-phenyl 4-chlorophenyl 428 phenyl CH₃ R SO₂ 1,4-phenyl 3,5-dichloro phenyl 429 phenyl CH₃ R SO₂ 1,4-phenyl 2,4-dichloro phenyl 430 phenyl CH₃ R SO₂ 1,4-phenyl 3,5-difluoro methylphenyl 432 phenyl CH₃ R SO₂ 1,4-phenyl 2-benzofuryl 433 phenyl CH₃ R SO₂ 1,4-phenyl 2-(t-butylamino sulfonyl)phenyl 434 phenyl CH₃ R SO₂ 1,4-phenyl 4-cyanophenyl 435 phenyl CH₃ R SO₂ 1,4-phenyl 3-cyanophenyl 436 phenyl CH₃ R SO₂ 1,4-phenyl 3-carboxyphenyl 437 phenyl CH₃ R SO₂ 1,4-phenyl 2[(di-i-propyl) aminocarbonyl] phenyl 438 phenyl CH₃ R SO₂ 1,4-phenyl 4-(3,5-dimethyl) isoxazol 439 phenyl CH₃ R SO₂ 1,4-phenyl 2-methoxy-5- formylphenyl 440 phenyl CH₃ R SO₂ 1,4-phenyl 4-pyridyl 441 phenyl CH₃ R SO₂ 1,4-phenyl 2,3,4-tri methoxyphenyl 442 phenyl CH₃ R SO₂ 1,4-phenyl phenoxathiinyl 443 phenyl CH₃ R SO₂ 1,4-phenyl 2-(5-formyl)furyl 444 phenyl CH₃ R SO₂ 1,4-phenyl 2-(4-methyl) thienyl 446 phenyl CH₃ R SO₂ 1,4-phenyl dibenzothienyl 447 phenyl CH₃ R SO₂ 1,4-phenyl dianthrenyl 448 phenyl CH₃ R SO₂ 1,4-phenyl dibenzothienyl 449 phenyl CH₃ R SO₂ 1,4-phenyl 3-benzothienyl 450 phenyl CH₃ R SO₂ 1,4-phenyl 3,4-dimethoxy phenyl 451 phenyl CH₃ R SO₂ 1,4-phenyl 2-fluorophenyl 452 phenyl CH₃ R SO₂ 1,4-phenyl 1-naphthyl 453 phenyl CH₃ R SO₂ 1,4-phenyl 4-methoxy phenyl 454 phenyl CH₃ R SO₂ 1,4-phenyl 3-fluoro-4- chlorophenyl 455 phenyl CH₃ R SO₂ 1,4-phenyl 2-nitrophenyl 456 phenyl CH₃ R SO₂ 1,4-phenyl 3-biphenyl 457 phenyl CH₃ R SO₂ 1,4-phenyl 2-(t-butylcarbonyl amino)-3-methoxy phenyl 458 phenyl CH₃ R SO₂ 1,4-phenyl 2-(t-butyl carbonyl amino)-5-methoxy phenyl 459 phenyl CH₃ R SO₂ 1,4-phenyl 2-(5-formyl)furyl 460 phenyl CH₃ R SO₂ 1,4-phenyl 2,5-dimethoxy phenyl 461 phenyl CH₃ R SO₂ 1,4-phenyl 2-(di(i-propyl) aminocarbonyl)-3- methoxyphenyl 462 phenyl CH₃ R SO₂ 1,4-phenyl 4-methylthio phenyl 463 phenyl CH₃ R SO₂ 1,4-phenyl 2,4,6-tri methylphenyl 464 phenyl CH₃ R SO₂ 1,4-phenyl 3-methylphenyl 465 phenyl CH₃ R SO₂ 1,4-phenyl 4-methylphenyl 466 phenyl CH₃ R SO₂ 1,4-phenyl 3-pyridyl 467 phenyl CH₃ R SO₂ 1,4-phenyl 3-aminophenyl 468 phenyl CH₃ R SO₂ 1,4-phenyl 3-methylcarbonyl aminophenyl 477 phenyl CH₃ R C(O) 1,4-phenyl 2-chlorophenyl 478 phenyl CH₃ R C(O) 1,4-phenyl 2-methylphenyl 479 phenyl CH₃ R C(O) 1,4-phenyl 3-fluorophenyl 480 phenyl CH₃ R C(O) 1,4-phenyl 2-bromophenyl 481 phenyl CH₃ R C(O) 1,4-phenyl 2,5-dichloro phenyl 521 phenyl CH₃ R SO₂ 1,4-phenyl 2-methyl-3- chlorophenyl 522 phenyl CH₃ R SO₂ 1,4-phenyl 2-chloro-5- methylphenyl 523 phenyl CH₃ R SO₂ 1,4-phenyl 2-methyl-5- chlorophenyl 524 phenyl CH₃ R SO₂ 1,4-phenyl 3-chloro-4- methylphenyl 525 phenyl CH₃ R SO₂ 1,4-phenyl 2-chloro-6- methylphenyl 526 phenyl CH₃ R SO₂ 1,4-phenyl 2-chloro-4- methylphenyl 550 3-trifluoro H — SO₂ 1,4-phenyl phenyl methyl phenyl 590 phenyl CH₃ R C(O)NH 1,4-phenyl phenyl 591 phenyl CH₃ S C(O)NH 1,4-phenyl phenyl

Cmpd # R⁴ m R⁵ R⁶ Stereo Y 378 1,5-n-pentyl 1 phenyl CH₃ R 2-methylphenyl 379 1,5-n-pentyl 1 phenyl CH₃ R 2-chlorophenyl 380 1,5-n-pentyl 1 phenyl CH₃ R 3-fluorophenyl 381 1,5-n-pentyl 1 phenyl CH₃ S 2-methylphenyl 382 1,5-n-pentyl 1 phenyl CH₃ S 2-chlorophenyl 383 1,5-n-pentyl 1 phenyl CH₃ S 3-fluorophenyl 352 1,5-n-pentyl 1 2-methoxyphenyl H — 2-methylphenyl 353 1,6-n-hexyl 1 2-methoxyphenyl H — 2-chlorophenyl 354 1,6-n-hexyl 1 2-methoxyphenyl H — 2-methoxyphenyl 355 1,6-n-hexyl 1 2-methoxyphenyl H — 2,4-dichlorophenyl 356 1,6-n-hexyl 0 2-methoxyphenyl H — 2-methylphenyl 357 1,6-n-hexyl 0 2-methoxyphenyl H — 2-chlorophenyl 358 1,6-n-hexyl 0 2-methoxyphenyl H — 2-methoxyphenyl 359 1,6-n-hexyl 0 2-methoxyphenyl H — 2,4-dichlorophenyl 396 1,6-n-hexyl 1 phenyl CH₃ R 2-methylphenyl 397 1,6-n-hexyl 1 phenyl CH₃ R 2-chlorophenyl 398 1,6-n-hexyl 1 phenyl CH₃ R 3-fluorophenyl 399 1,6-n-hexyl 1 phenyl CH₃ S 2-methylphenyl 400 1,6-n-hexyl 1 phenyl CH₃ S 2-chlorophenyl 401 1,6-n-hexyl 1 phenyl CH₃ S 3-fluorophenyl

Cmpd # R⁴ R⁵

X 406 1,4-n-butyl 2-methoxyphenyl 1-phenyl 2,3-dichloro 407 1,6-n-hexyl 2-methoxyphenyl 1-phenyl 2,3-dichloro 408 1,4-n-butyl 3,4-methylene 8-quinolinyl — dioxyphenyl 409 1,6-n-hexyl 3,4-methylene 8-quinolinyl — dioxyphenyl

Cmpd # m Y 151 1 2-methylphenyl 152 1 3-thienyl 153 1 2-methoxyphenyl 154 1 4-fluorophenyl 155 1 2,4-dimethoxyphenyl 156 1 4-methoxyphenyl 157 1 4-methylphenyl 158 1 1-naphthyl 159 1 2-chlorophenyl 160 1 3-pyridyl 161 1 2-thienyl 162 1 3-acetamidophenyl 163 1 phenyl 164 1 4-chlorophenyl 165 1 4-[3,5-dimethylisoxazolyl] 166 1 3-chlorophenyl 167 1 4-cyanophenyl 168 1 4-pyridyl 169 1 3-methoxyphenyl 170 1 3-aminophenyl 171 1 3-fluorophenyl 172 1 2-fluorophenyl 173 1 3,4-methylenedioxyphenyl 174 0 2-methylphenyl 175 0 3-thienyl 176 0 2-methoxyphenyl 177 0 4-fluorophenyl 178 0 2,4-dimethoxyphenyl 179 0 4-methoxyphenyl 180 0 4-methylphenyl 181 0 1-naphthyl 182 0 2-chlorophenyl 183 0 3-pyridyl 184 0 2-thienyl 185 0 3-acetamidophenyl 186 0 phenyl 187 0 4-chlorophenyl 188 0 4-[3,5-dimethylisoxazolyl] 189 0 3-chlorophenyl 190 0 4-cyanophenyl 191 0 4-pyridyl 192 0 3-methoxyphenyl 193 0 3-aminophenyl 194 0 3-fluorophenyl 195 0 2-fluorophenyl 196 0 3,4-methylenedioxyphenyl

Cmpd # R⁵

X 410 2-methoxyphenyl 1-phenyl 2,3-dichloro 411 3,4-methylenedioxyphenyl 8-quinolinyl —

Cmpd # Stereo Y 366 R 2-methylphenyl 367 R 2-chlorophenyl 368 R 3-fluoophenyl 369 S 2-methylphenyl 370 S 2-chlorophenyl 371 S 3-fluorophenyl

Cmpd # Y 320 2-methylphenyl 321 2-chlorophenyl 322 3-fluorophenyl

Cmpd # Stereo n X 431 R 1 4-n-butyl 445 R 0 — 469 R 1 4-bromo 470 S 1 4-bromo 551 R 1 4-methoxy 552 R 1 4-trifluoromethyl 553 R 1 4-isopropyl 554 R 1 4-n-propyl 555 R 1 4-t-butyl 556 R 1 4-n-pentyl 557 R 1 3-methoxy 558 S 1 4-methoxy 559 S 1 4-trifluoromethyl 560 S 1 4-isopropyl 561 S 1 4-n-propyl 562 S 1 4-t-butyl 563 S 1 4-n-pentyl 564 S 1 3-methoxy

Cmpd # R¹ R² Stereo Y 471 methyl methyl R 2-chlorophenyl 472 ethyl ethyl R 2-chlorophenyl 473 H methylcarbonyl R 2-chlorophenyl 474 methyl methyl S 2-methylphenyl 475 ethyl ethyl S 2-methylphenyl 476 H methylcarbonyl S 2-methylphenyl

Cmpd # R⁴ L 483 —CH₂-(1,4-phenyl)-CH₂— 4-methoxyphenylethyl 484 —CH₂-(1,4-phenyl)-CH₂— 3,6-dimethoxyphenylethyl 485 —CH₂-(1,4-phenyl)-CH₂— 2,3-dimethoxyphenylethyl 486 —CH₂-(1,4-phenyl)-CH₂— 1-cyclohexenylethyl 487 —CH₂-(1,4-phenyl)-CH₂— 3-bromo-4,5-dimethylphenylethyl 488 —CH₂-(1,4-phenyl)-CH₂— 2-chlorophenylethyl 489 —CH₂-(1,4-phenyl)-CH₂— 3-chlorophenylethyl 490 —CH₂-(1,4-phenyl)-CH₂— 2,4-dichlorophenylethyl 491 —CH₂-(1,4-phenyl)-CH₂— 2,6-dichlorophenylethyl 492 —CH₂-(1,4-phenyl)-CH₂— 2-trifluoromethylphenylethyl 493 —CH₂-(1,4-phenyl)-CH₂— 3,4-dimethylphenylethyl 494 —CH₂-(1,4-phenyl)-CH₂— 3,5-dimethylphenylethyl 495 —CH₂-(1,4-phenyl)-CH₂— 3-methoxyphenylethyl 496 —CH₂-(1,4-phenyl)-CH₂— 3-(2-chlorophenyl)-4,5- dimethoxyphenylethyl 501 n-hexyl 3,4-dimethoxyphenylethyl 502 n-hexyl 4-methoxyphenylethyl 503 n-hexyl 2,3-dimethoxyphenylethyl 504 n-hexyl 3-bromo-4,5- dimethoxyphenylethyl 505 n-hexyl 2-chlorophenylethyl 506 n-hexyl 3-chlorophenylethyl 507 n-hexyl 2,4-dichlorophenylethyl 508 n-hexyl 2,6-dichlorophenylethyl 509 n-hexyl 3,5-dimethoxyphenylethyl 510 n-hexyl 3-methoxyphenylethyl 511 n-hexyl 2,5-dimethoxyphenylethyl 512 n-hexyl 1-cyclohexenylethyl 513 n-hexyl 3-(2-chlorophenyl)-3,4- dimethoxyphenylethyl 514 n-hexyl 2-fluorophenylethyl 515 n-hexyl 2-trifluoromethylphenylethyl 527 —CH₂-(1,4-phenyl)-CH₂— 2-nitrophenylethyl 528 —CH₂-(1,4-phenyl)-CH₂— 2-aminophenylethyl 529 —CH₂-(1,4-phenyl)-CH₂— 2-dimethylaminophenylethyl 530 —CH₂-(1,4-phenyl)-CH₂— 2-(methylcarbonylamino) phenylethyl 531 —CH₂-(1,4-phenyl)-CH₂— 2-(methylsulfonylamino) phenylethyl 532 —CH₂-(1,4-phenyl)-CH₂— CH₂—C(CH₃)₂-phenyl 533 —CH₂-(1,4-phenyl)-CH₂— CH₂—C(OCH₃)-phenyl 534 —CH₂-(1,4-phenyl)-CH₂— CH₂—CH(CH₃)-(2-methoxyphenyl) 535 —CH₂-(1,4-phenyl)-CH₂— bicyclo[4.2.0]octa-1,3,5-triene 536 —CH₂-(1,4-phenyl)-CH₂— CH₂—CH(cyclohexyl)-phenyl 537 —CH₂-(1,4-phenyl)-CH₂— CH₂—CH(cyclobutyl)-phenyl 538 —CH₂-(1,4-phenyl)-CH₂— CH₂—CH(ethyl)-phenyl 539 —CH₂-(1,4-phenyl)-CH₂— 2,3-dihydro-1H-indene 540 —CH₂-(1,4-phenyl)-CH₂— CH(phenyl)₂ 541 —CH₂-(1,4-phenyl)-CH₂— 2-methylphenylethyl 542 —CH₂-(1,4-phenyl)-CH₂— 3-fluorophenylethyl 543 —CH₂-(1,4-phenyl)-CH₂— 3,4-methylenedioxyphenyl 544 —CH₂-(1,4-phenyl)-CH₂— 2-pyridylethyl 545 —CH₂-(1,4-phenyl)-CH₂— 2-thienylethyl 546 —CH₂-(1,4-phenyl)-CH₂— 2-(N-methyl)-pyrrolidinylethyl 547 —CH₂-(1,4-phenyl)-CH₂— phenylpropyl 548 —CH₂-(1,4-phenyl)-CH₂— 2-ethoxyphenylethyl 549 —CH₂-(1,4-phenyl)-CH₂— 3,4-dichlorophenylethyl 572 n-hexyl CH₂—CH(OCH₃)-phenyl 573 n-hexyl CH₂—CH(CH₃)-(2-methoxyphenyl) 574 n-hexyl bicyclo[4.2.0]octa-1,3,5-triene 575 n-hexyl CH₂—CH(cyclohexyl)-phenyl 576 n-hexyl CH₂—CH(cyclobutyl)-phenyl 577 n-hexyl CH₂—CH(ethyl)-phenyl 578 n-hexyl 2,3-dihydro-1H-indene 579 n-hexyl CH₂—CH(phenyl)₂ 580 n-hexyl 2-methylphenylethyl 581 n-hexyl 3-fluorophenylethyl 582 n-hexyl 3,4-methylenedioxyphenyl 583 n-hexyl 2-pyridylethyl 584 n-hexyl 2-thienylethyl 585 n-hexyl 2-(N-methylpyrrolidinyl)ethyl 586 n-hexyl phenylpropyl 587 n-hexyl 2-ethoxyphenylethyl 588 n-hexyl 3,4-dichlorophenylethyl 589 n-hexyl 3-trifluoromethylphenylethyl

Cmpd # Stereo Y 497 R 2-chlorophenyl 498 R 2-methylphenyl 499 R 3-fluorophenyl 500 S 2-chlorophenyl

[0109] In a particularly preferred embodiment of the present invention are compounds of the formula (I) as enumerated in Table 2 below: TABLE 2 (Structure and Compound #)

and stereoisomers and pharmaceutically acceptable salts or esters thereof.

[0110] For the compounds listed in Table 3 below, as well as all compounds listed in Table 1 and 2 above, structures were confirmed via molecular weight determination using an electro-spray mass spectrometer in positive mode and via HPLC retention time on a reversed phase column. TABLE 3 Cmpd Meas MW HPLC RT # MH⁺ (min) 39 460.47 40 500.13, 502.10 41 528.56, 530.27 42 528.48, 530.28 43 494.43, 496.16 44 528.05, 530.16 45 510.29 46 494.32, 496.16 47 494.23, 496.16 48 534.05, 536.12 49 528.07, 530.11 50 528.07, 530.12 51 528.07, 530.13 52 528.07, 530.14 53 528.07, 530.15 54 474.62, 476.30 55 474.62, 476.31 56 490.62, 492.37 57 510.57, 512.37 58 478.66, 480.23 59 520.45, 522.37 60 520.56, 522.33 61 505.3 62 505.3 63 505.3 64 586.45 65 516.7 66 535.41 67 504.67, 506.39 68 573.51 69 478.68, 480.35 70 478.68, 480.36 71 3.325 72 3.348 73 3.315 74 52.45, 524.28 75 514.34, 516.29 76 538.47, 540.32 77 526.58, 528.32 78 568.03 79 538.42, 540.36 80 522.57, 524.34 81 558.56, 560.31 82 542.26, 544.13 83 509.14 84 514.16 85 565.5, 567.30 86 508.47, 510.29 87 542.19, 544.07 88 527.44, 530.22 89 3.206 90 533.40, 535.30 91 509.14 92 538.46, 540.34 93 523.16 94 536.54 95 528.31, 530.28 96 552.48, 55434 97 540.44, 542.34 98 582.07 99 552.67, 554.32 100 536.53, 538.37 101 572.43, 574. 23 102 556.25, 558.04 103 523.16 104 528.3 105 3.158 106 522.42 107 556.20, 558.01 108 541.34, 543.37 109 3.293 110 547.22 111 523.2 112 552.37 113 537.18 114 508.0, 510.0 115 536.1 116 536.1 117 502.1, 504.1 118 536.0, 538.0 119 518.1 120 502.1, 504.1 121 528.1 122 536.0, 538.0 123 536.0, 538.1 124 536.0, 538.2 125 536.0, 538.3 126 541.9, 543.9 127 482.2 128 498.2 129 518.1 130 486.2 131 486.2 132 486.2 133 528.1 134 513.1 135 513.1 136 513.1 137 594 138 524.2 139 543.1 140 512.2 141 2.946 142 581 143 536.1 144 552 145 551 146 598.1 147 474.1 148 482.2 149 502.1, 504.1 150 468.1 151 508.2 152 500.1 153 524.1 154 512.1 155 554.1 156 524.1 157 508.2 158 544.1 159 528.1, 530.1 160 495.2 161 500.1 162 551.1 163 494.2 164 528.1 165 513.1 166 528.1, 530.0 167 519.1 168 495.2 169 524.1 170 509.1 171 512.1 172 512.1 173 538.1 174 494.2 175 486.1 176 510.1 177 498.1 178 540.1 179 510.1 180 494.2 181 530.1 182 514.1, 516.2 183 481.1 184 486.1 185 537.1 186 480.2 187 514.1, 516.0 188 499.1 189 514.1, 516.0 190 505.1 191 481.1 192 510.1 193 495.2 194 498.1 195 498.1 196 524.1 197 528.2 198 562.1, 564.0 562.4, 564.4 199 562.1, 564.1 200 558.1 201 558.1 202 558.1 203 546.1 204 546.1 205 542.1 206 542.1 207 528.1 208 562.1, 564.0 209 562.1, 564.1 210 558.1 211 558.1 212 558.1 213 546.1 214 546.1 215 542.1, 542.5 216 542.1 217 3.418 218 3.509 219 3.403 220 3.413 221 3.450 222 3.465 223 3.539 224 3.575 225 578.1, 580.1 226 574.1 227 559.1 228 562.1 229 562.1 230 588.1 231 578.1, 580.1 232 544.1 233 563.1 234 569.1 235 545.1 236 634.3 237 569.1 238 604.2 239 612.1, 614.1 240 612.2 241 612.2 242 612.2 243 558.1 244 558.2 245 550.1 246 574.2 247 562.1 248 574.2 249 558.2 250 594.2 251 578.1, 580.1 252 545.2 253 578.1, 580.1 254 574.2 255 559.2 256 562.1 257 562.1 258 588.2 259 578.1 260 544.2 261 563.2 262 569.2 263 545.2 264 534.4 265 569.1 266 604.3, 605.3 267 612.3 268 612.3 269 612.3 270 558.2 271 554.0, 556.1 272 564.1 273 556.1 274 580.2 275 568.1 276 580.2 277 564.1 278 600.2 279 584.1, 586.1 280 551.1 281 584.1, 586.1 282 580.2 283 565.1 284 568.1 285 568.1 286 594.2 287 584.1, 586.1 288 550.1 289 569.1 290 575.1 291 551.1 292 640.4 293 575.1 294 3.315 295 610.2 296 4.021 297 618.3 298 618.2 299 618.2 300 564.1 301 546 302 564 303 595.9, 597.9 304 596 305 570 306 546 307 564 308 595.9, 597.9 309 596 310 570 311 542 312 561.9, 563.9 313 546 314 576.0, 578.0 315 595.9, 597.9 316 579.9, 581.9 317 588.0, 590.0 318 608.0, 610.0 319 592.0, 594.0 320 540 321 559.9, 561.9 322 544 323 528 324 548.0, 549.9 325 532 336 564.1 337 584.1, 586.1 338 580.1 339 618.1, 620.1 340 550.1 341 570.0, 572.0 342 566.1 343 604.1, 606.1 344 558.1 345 578.0, 580.0 346 574.1 347 612.1, 614.1 348 544.1 349 564.0, 566.0 350 560.1 351 598.0, 600.0 352 538.2, 538.2 353 558.1, 560.1 558.1, 560.1 354 554.1 355 592.0, 594.0 356 524.2 357 544.1, 546.1 358 540.1 359 578.0, 580.0 366 574.2 367 594.1, 596.1 368 578.1 369 574.1 370 594.1, 596.1 371 578.1 372 548.2 373 568.1, 570.1 568.1, 570.1 374 552.1 375 548.2 376 568.1, 570.0 377 552.1 378 508.2 379 526.1 380 512.1 381 508.2 382 528.1, 530.1 383 512.1 384 548.2 385 568.1, 570.0 386 552.1 387 548.1 388 568 389 552.1 390 542.1, 542.1 391 564 392 546, 546.0 393 542.1 394 562.0, 564.0 395 546 396 522.2, 522.2 397 542.1, 544.1 542.1, 544.1 398 526.1, 526.1 399 522.2 400 542.1, 544.1 401 526.1 402 528.1, 530.2 412 528.2 413 573.1 414 546.1 415 542.2 416 596.1 417 596.1 418 562.1 419 558.1 420 596.1 421 558.1 422 612.1 423 546.1 424 578.1 425 580 426 606 427 562 428 596 429 596 430 664 431 508.1 432 568.1 433 663 434 553.1 435 553.1 436 572 437 655.1 438 547.1 439 586 440 529.1 441 618.1 442 650 443 532 444 548.1 445 452.1 446 634.1 447 666 448 634.1 449 584 450 588.1 451 546.1 452 578.1 453 558.1 454 580 455 573 456 604.1 457 657.1 458 657.1 459 546.1 460 588.1 461 685.2 462 574 463 570.1 464 542.2 465 542.1 466 539.2 467 543.2 468 585.1 469 530.31, 532.31 470 530.31, 532.32 471 590.54, 592.54 472 618.59, 620.57 473 604.52, 606.54 474 570.59 475 598.64 476 584.57 477 526.5, 528.5 478 506.6 479 510.6 480 606.5, 608.5 481 614.5, 616.5 483 578.5, 580.4 484 608.5, 610.5 485 608.5, 610.5 486 552.5, 554.5 487 686.5, 688.5 488 582.4, 584.4 489 582.4, 584.4 490 616.5, 618.5 491 616.5, 618.4 492 616.5, 618.5 493 622.6, 624.6 494 608.5, 610.5 495 578.4, 580.4 496 718.6, 720.6 497 636.7 498 616.7 499 620.9 500 636.7 501 602.6, 604.5 502 558.5, 560.5 503 588.5, 590.5 504 666.6, 668.6 505 562.4, 564.4 506 562.4, 564.4 507 596.4, 598.4 508 596.5, 598.5 509 588.5, 590.5 510 558.5, 560.5 511 588.5, 560.5 512 532.5, 534.5 513 698.7, 700.7 514 546.5, 548.5 515 596.5, 598.5 521 576.5, 578.5 522 576.5, 578.5 523 576.5, 578.6 524 576.5, 578.7 525 576.5, 578.8 526 576.5, 578.9 527 592.9, 594.9 528 563.0, 565.5 529 590.9, 592.9 530 604.9, 606.9 531 640.9, 642.9 532 576.0, 577.9 533 578, 0, 580.0 534 592.0, 594.0 535 560.0, 562.0 536 616.0, 618.0 537 587.9, 589.9 538 576.0, 578.0 539 560.0, 562.0 540 623.9, 625.9 541 562.0, 564.0 542 566.0, 567.9 543 591.9, 593.9 544 549.0, 551.0 545 554.0, 555.9 546 555.0, 557.0 547 562.0, 564.0 548 591.9, 593.9 549 615.8, 617.8 550 582.6 551 482.6 552 520.5 553 494.6 554 494.6 555 508.6 556 522.6 557 482.6 558 482.6 559 520.5 560 494.5 561 494.6 562 508.6 563 522.6 564 482.5 572 558.4, 560.0 573 572.0, 574.0 574 540.5, 542.1 575 596.4, 598.0 576 569.2, 571.0 577 557.0, 559.1 578 540.5, 542.1 579 604.3 580 542.4, 544.1 581 547.1, 549.0 582 572.0, 574.0 583 529.0, 531.0 584 534.0, 536.0 585 535.1, 537.1 586 542.5, 544.1 587 572.0, 574.0 588 596.0, 597.9 589 596.3, 597.9 590 507.6 591 507.6

[0111] The salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts.” Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following:

[0112] acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

[0113] The pharmaceutically acceptable esters of the novel compounds of the present invention include such as would be readily apparent to a medicinal chemist, and include, for example, those described in detail in U.S. Pat. No. 4,309,43, Column 9, line 61 ot Column 12, line 51, which is incorporated herein by reference. Included within such pharmaceutically acceptable esters are those hydrolyzed under physiological conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, and those described I detail in U.S. Pat. No. 4,479,947, which is incorporated herein by reference.

[0114] The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

[0115] Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

[0116] Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

[0117] It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.

[0118] Abbreviations used in the specification, particularly the Schemes and Examples, are as follows: TABLE 4 Abbreviation Definition BOC = Butoxycarbonyl Cmpd # = Compound Number DCE = Dichloroethane DCM = Dichloromethane DIEA = Diisopropylethylamine DMAC = Dimethylacetamide DMAP = 4-Dimethylaminopyridine DMF = Dimethylformamide DMSO = Dimethylsulfoxide EDTA = Ethylenediamine-N,N,N″,N″-tetraacetic acid Fmoc = 9-Fluorenyl methoxycarbonyl h-FSHR = human Follicle Stimulating Hormone Receptor FMPB = 4-(4-Formyl-3-methoxyphenyoxy)butyryl HATU = 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HPLC RT = High Pressure Liquid Chromatography Retention Time Mol. Wt. = Measured Molecular Weight PBF = 2,2,4,6,7-Pentamethyldihydrobenzofuran-5-sulfonyl Stereo = Optical Configuration of Stereogenic Center TMOF = Trimethylorthoformate

[0119] The substituted aminoalkylamide derivatives of this invention are capable of inhibiting follicle stimulating hormone (FSH) to achieve the desired pharmacological effect. With an effective amount of the substituted aminoalkylamide derivative compounds dispersed in a pharmaceutical composition as an active ingredient, the pharmaceutical composition is introduced as a unit dose into an afflicted mammal.

[0120] The term “unit dosage” and its grammatical equivalent is used herein to refer to physically discrete units suitable as unitary dosages for human patients and other warm blooded mammals, each unit containing a predetermined effective, pharmacologic amount of the active ingredient calculated to produce the desired pharmacological effect in association with the required physiologically tolerable carrier, e.g., a diluent or a vehicle. The specifications for the novel unit dosage forms suitable for use herein are dictated by and are directly dependent on (a) the unique characteristics of the active ingredient, and (b) the limitations inherent in the art of compounding such an active ingredient for therapeutic use in humans and other mammals. Examples of suitable unit dosage form in accord with this invention are tablets, capsules, pills, powder packets, granules, wafers, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation and the like. The active ingredient is referred to herein as being dispersed in the carrier. The dispersion form can be a simple admixture, a non-settling dispersion as in the case of certain emulsions, or as an ultimate dispersion, a true solution.

[0121] The amount of active ingredient that is administered in vivo depends on the age and weight of the mammal treated, the particular medical condition to be treated, the frequency of administration, and the route of administration. The dose range can be about 0.01 to about 500 milligrams per kilogram of body weight, more preferably about 0.1 to about 50 milligrams per kilogram of body weight and most preferably about 0.1 to about 25 milligrams per kilogram of body weight. The human adult dose is in the range of about 10 to about 2000 milligrams daily, given as a single dose or in 3 or 4 divided doses. Veterinary dosages correspond to human dosages with the amounts administered being in proportion to the weight of the animal as compared to adult humans. When the compounds are employed to treat FSH receptor mediated diseases or disorders the dosage range can be about 0.01 to about 200 mg/kg. The preferred dosage range is from about 0.5 to about 100 mg/kg.

[0122] Physiologically tolerable carriers are well known in the art. Carriers may be divided into liquid and solid carriers.

[0123] Exemplary of liquid carriers are aqueous solutions that contain no materials in addition to the substituted aminoalkylamide derivative compound, or contain a buffer such as sodium phosphate ay a physiological pH value, saline and the like. Liquid compositions can also contain liquid phases in addition to and to the exclusion of water. Exemplary of such additional liquid phases are glycerin and vegetable oils such as cottonseed oil.

[0124] Exemplary solid carriers (diluents) include those materials usually used in the manufacture of pills or tablets, and include corn starch, lactose, dicalcium phosphate, thickeners, such as tragacanth and methylcellulose U.S.P., finely divided SiO₂, polyvinylpyrrolidone, magnesium stearate and the like. Antioxidants such as methylparaben and propylparaben can be present in both solid and liquid compositions, as can sweeteners such as cane or beet sugar, sodium saccharin, sodium cyclamate and the dipeptide methyl ester sweetener sold under the trademark NUTRASWEET (aspartame) by G. D. Searle Co.

[0125] The pharmaceutical composition can be administered orally, topically or by injection, by means well known in the art. In preferred practice, the composition is administered orally as a tablet, capsule or aqueous dispersion. The pharmaceutical composition is maintained within the mammal until the substituted aminoalkylamide derivative compound is cleared from the mammal's body by natural means such as excretion or metabolism.

[0126] Compositions for injection may be prepared in unit dosage form in ampules or in multidose containers. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents. Alternatively, the active ingredient may be in a powder form for reconstitution, at the time of delivery, with a suitable vehicle, such as sterile water. Topical formulations may be formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints, or powders.

[0127] The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phophatidylcholines.

[0128] Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyl-eneoxidepolylysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

[0129] Inasmuch as a pharmaceutical composition can be administered 3 to 4 times daily (per 24 hour period), the method of treating a disorder of condition mediated by FSH can include administering the pharmaceutical composition a plurality of times into the treated mammal over a time period of weeks, months and years.

[0130] Disorders or conditions mediated by the FSH receptor include uterine fibroids, endometriosis, polycystic ovarian disease, dysfunctional uterine bleeding, breast cancer and ovarian cancer; depletion of oocytes (a common side effect of chemotherapy or similar treatment); spermatocyte depletion; or for female and male contraception.

[0131] The following examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.

EXAMPLE 1

[0132]

[0133] A. Preparation of Amino Carbamate Resin

[0134] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0135] B. Coupling of Bromoacetic Acid

[0136] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0137] C. Preparation of the Optically Pure Secondary Amine on Resin

[0138] The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added (R)-β-methylphenethylamine (5.408 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0139] D. Preparation of 4-Bromophenylsulfonamide Resin

[0140] The optically pure resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0141] E. Preparation of Sulfonamide Resin

[0142] The N-(R)-β-methylphenthyl-4-bromophenyl-sulfonamide resin (from D) was split into 10 portions, each containing 0.133 millimole of resin. To one portion was added 2-chlorobenzeneboronic acid (0.076 g, 0.399 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0143] F. Cleavage of the Resin Support

[0144] The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0145] Compounds 301-310 were prepared according to the above procedure with appropriate selection and substitution of suitably substituted benzeneboronic acid in Step E.

[0146] Compounds 311-319 were similarly prepared according to the procedure above with appropriate selection and substitution of a racemic mixture of suitably substituted phenethylamine in Step C and appropriate selection and substitution of suitably substituted benzeneboronic acid in Step E.

[0147] Compounds 412 through 468 may similarly be prepared according to the procedure described above, with appropriate selected and substitution of a suitably substituted boronic acid in Step E.

[0148] Compounds 469-470 were similarly prepared according to the procedure above, with appropriate selection and substitution of reagents. Compound 469 was prepared from the product of Step D, Compound 470 was prepared by substituting (S)-β-methylphenethylamine for (R)-β-methylphenethylamine in Step C.

[0149] Compounds 483-496 were similarly prepared according to the procedure above, with appropriate selection and substitution of suitably substituted phenethylamines in step C. Compounds 527-549 were similarly prepared according to the procedure above with appropriate selection and substitution of suitably substituted phenethylamines in step C.

[0150] Compounds 522-526 were similarly prepared according to the procedure above, with appropriate selection and substitution of reagents.

EXAMPLE 2

[0151]

[0152] A. Preparation of Amino Carbamate Resin.

[0153] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0154] B. Coupling of Bromoacetic Acid.

[0155] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0156] C. Preparation of the Secondary Amine on Resin

[0157] The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added 2-(2-methoxy)phenethylamine (5.408 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0158] D. Preparation of Sulfonamide Resin

[0159] The resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) followed by 5-bromo-2-thiophenesulfonyl chloride (5.23 g, 20.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0160] E. Preparation of Substituted Phenylsulfonamide Resin

[0161] The 4-bromophenylsulfonamide resin (from D) was split into 23 portions, each containing 0.174 millimole of resin. To one portion was added 2-methylbenzeneboronic acid (0.089 g, 0.522 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.020 g, 0.0174 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (1.086 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0162] F. Cleavage of the Resin Support

[0163] The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0164] Compounds 271, 273-300 were prepared according to the process above with appropriate selection and substitution of a suitably substituted boronic acid in Step E.

EXAMPLE 3

[0165]

[0166] A. Preparation of Amino Carbamate Resin.

[0167] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0168] B. Coupling of Bromoacetic Acid.

[0169] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0170] C. Preparation of the Secondary Amine

[0171] The 2-bromoacetylated resin (from B) was swelled in DMSO (approximately 150 ml). To the suspension was added phenethylamine (6.045 g, 40 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0172] D. Preparation of Bromophenylsulfonamide Resin

[0173] The resin-bound secondary amine (from C) was swelled in DCM (approximately 200 ml). To the suspension was added pyridine (3.19 g) followed by 4-bromophenylsulfonylchloride (5.1 g, 20 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0174] E. Preparation of Sulfonamide Resin

[0175] The resin-bound secondary amine (from D) was split into 10 portions, each containing 0.133 millimole of resin. To one portion was 2-methylbenzeneboronic acid (0.056 g, 0.399 millimoles). To the solution was then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0176] F. Cleavage of the Resin Support

[0177] The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0178] Compounds 197, 199-204, 206-216 and 323-325 were prepared according to the above procedure, with appropriate selection and substitution of a suitably substituted benzeneboronic acid in Step E Compounds 412 through 468 may alternatively be prepared according to the procedure described in Example 3 above, with substitution of (R)-β-methylphenylethylamine in Step C and appropriate selected and substitution of a suitably substituted boronic acid in Step E.

EXAMPLE 4

[0179]

[0180] A. Preparation of Amino Carbamate Resin.

[0181] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0182] B. Coupling of Bromoacetic Acid.

[0183] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0184] C. Preparation of the Secondary Amine

[0185] (Displacement of Bromide by 2-(2-methoxy)phenethylamine)

[0186] The 2-bromoacetylated resin (from B) was swelled in DMSO (approximately 150 ml). To the suspension was added 2-(2-methoxy)phenethylamine (6.045 g, 40 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0187] D. Preparation of Bromophenylsulfonamide Resin

[0188] The resin-bound secondary amine (from C) was swelled in DCM (approximately 200 ml). To the suspension was added pyridine (3.19 g) followed by 3-bromophenylsulfonylchloride (5.1 g, 20 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0189] E. Preparation of Sulfonamide Resin

[0190] The 3-bromophenylsolfonamide resin (from D) was split into 30 portions, each containing 0.133 millimoles of resin. To one portion was added 2-thiopheneboronic acid (0.051 g, 0.399 millimoles). To the solution was then added palladium tetrakistriphenylphosphine (0.0154 g, 0.133 millimoles), DME (2.5 ml) and 2M sodium carbonate solution in water (0.830 ml). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0191] F. Cleavage of the Resin Support

[0192] The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0193] Compounds 10-19, 145-146, 217, 219-244 and 246-270 were prepared according to the above procedure with appropriate selection and substitution of bromophenylsulfonyl chloride in step D and by appropriate selection and substitution of a suitably substituted boronic acid in step E.

EXAMPLE 5

[0194]

[0195] A. Preparation of Amino Carbamate Resin

[0196] Wang p-nitrophenylcarbonate resin (4.0 millimole) was swelled in DMF (200 mL). To the suspension was added 1,4-xylenediamine (5.45 g, 40.0 millimole) dissolved in DMF (75 mL). The mixture was shaken for 24 hours. The solvent was removed by filtration. The resin was washed with 3 portions of DMF, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0197] B. Coupling of Bromoacetic Acid

[0198] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0199] C. Preparation of the Secondary Amine on Resin

[0200] The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added 2-methoxyphenethylamine (6.05 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0201] D. Preparation of 2-Bromophenylsulfonamide Resin

[0202] The resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) followed by 2-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0203] E. Preparation of Substituted Phenylsulfonamide Resin

[0204] The 2-bromophenylsulfonamide resin (from D) was split into 23 portions, each containing 0.174 millimole of resin. To one portion was added 2-methylbenzneboronic acid (0.071 g, 0.522 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.020, 0.0174 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (1.086 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0205] F. Cleavage of the Resin Support

[0206] The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

EXAMPLE 6

[0207]

[0208] A. Preparation of Amino Carbamate Resin.

[0209] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0210] B. Coupling of Bromoacetic Acid.

[0211] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0212] C. Preparation of the Secondary Amine

[0213] (Displacement of Bromide by 2-(2-methoxy)phenethylamine)

[0214] The 2-bromoacetylated resin (from B) was swelled in DMSO (approximately 150 ml). To the suspension was added 2-(2-methoxy)phenethylamine (6.045 g, 40 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0215] D. Preparation of Sulfonamide Resin

[0216] The resin bound secondary amine (from C) was split into 36 portions each containing 0.111 millimole of resin. One portion was swelled in DCM (1.5 ml). To the suspension was added pyridine (0.089 g), followed by 5-chlorothiophene-2-sulfonyl chloride (0.121 g, 0.556 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0217] E. Cleavage of the Resin Support

[0218] The product was cleaved from the resin using a cleaving cocktail solution of 90:10 TFA:water. The cleavage solution was evaporated. The product was purified by semi-preparative reversed phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product wa lyophilized and analyzed by ES/MS and reversed phase HPLC.

[0219] Compounds 115-144 and 147-150 were prepared according the above procedure with appropriate selection and substitution of a suitably substituted sulfonyl chloride in Step D.

[0220] Compounds 550-564 were similarly prepared according to the procedure above with appropriate selection and substitution of suitably substituted phenethylamines in step C and appropriate selection and substitution of suitably substituted sulfonyl chlorides in step D.

EXAMPLE 7

[0221]

[0222] A. Preparation of Amino Carbamate Resin

[0223] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-cyclohexylmethylamine (5.69 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0224] B. Coupling of Bromoacetic Acid

[0225] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0226] C. Preparation of the Optically Pure Secondary Amine on Resin

[0227] The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added (R)-β-methylphenethylamine (5.408 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0228] D. Preparation of 4-Bromophenylsulfonamide Resin

[0229] The optically pure resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0230] E. Preparation of Substituted Phenylsulfonamide Resin

[0231] The N-(R)-β-methylphenthyl-4-bromophenyl-sulfonamide resin (from D) was split into 10 portions, each containing 0.133 millimole of resin. To one portion was 2-methylbenzeneboronic acid (0.076 g, 0.399 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0232] F. Cleavage of the Resin Support

[0233] The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0234] Compounds 373-377 were prepared according to the procedure above with suitable selection and substitution of a suitably substituted benzeneboronic acid in Step E.

EXAMPLE 8

[0235]

[0236] A. Preparation of Amino Carbamate Resin.

[0237] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-cyclohexylmethylamine (5.69 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0238] B. Coupling of Bromoacetic Acid.

[0239] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0240] C. Preparation of the Secondary Amine

[0241] (Displacement of Bromide by 2-(2-methoxy)phenethylamine)

[0242] The 2-bromoacetylated resin (from B) was swelled in DMSO (approximately 150 ml). To the suspension was added 2-(2-methoxy)phenethylamine (6.045 g, 40 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0243] D. Preparation of Bromophenylsulfonamide Resin

[0244] The resin-bound secondary amine (from C) was swelled in DCM (approximately 200 ml). To the suspension was added pyridine (3.19 g) followed by 4-bromophenylsulfonylchloride (5.1 g, 20 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0245] E. Preparation of Sulfonamide Resin

[0246] The 4-bromophenylsolfonamide resin (from D) was split into 30 portions, each containing 0.133 millimoles of resin. To one portion was added 3-trifluorobenzeneboronic acid (0.076 g, 0.399 millimoles). To the solution was then added palladium tetrakistriphenylphosphine (0.0154 g, 0.133 millimoles), DME (2.5 ml) and 2M sodium carbonate solution in water (0.830 ml). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0247] F. Cleavage of the Resin Support

[0248] The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0249] Compounds 1-9, 20-28 and 30-38 were prepared according to the procedure above with appropriate selection and substitution of methoxybenzylamine or methoxyphenethylamine in Step C above, and appropriate selection and substitution of a suitably substituted benzeneboronic acid in Step E above.

EXAMPLE 9

[0250]

[0251] A. Preparation of Amino Carbamate Resin

[0252] Wang p-nitrophenylcarbonate resin (4.0 millimole) was swelled in DMF (200 mL). To the suspension was added 1,4-cyclohexylmethylamine (5.69 g, 40.0 millimole) dissolved in DMF (75 mL). The mixture was shaken for 24 hours. The solvent was removed by filtration. The resin was washed with 3 portions of DMF, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0253] B. Coupling of Bromoacetic Acid

[0254] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0255] C. Preparation of the Secondary Amine on Resin

[0256] The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added 2-methoxybenzylamine (5.226 mL, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0257] D. Preparation of Sulfonamide Resin

[0258] The resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) followed by 5-bromo-2-thiophenesulfonyl chloride (5.23 g, 20.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0259] E. Preparation of Substituted Phenylsulfonamide Resin

[0260] The 4-bromophenylsulfonamide resin (from D) was split into 23 portions, each containing 0.174 millimole of resin. To one portion was added 5-(2-methylthiopyrimidyl)boronic acid (0.089 g, 0.522 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.020, 0.0174 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (1.086 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0261] F. Cleavage of the Resin Support

[0262] The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0263] Compounds 39-72 were similarly prepared according to the procedure above with appropriate selection and substitution of suitably substituted bromo-sulfonyl chloride in Step C above, and appropriate selection and substitution of a suitably substituted benzeneboronic acid in Step E above.

EXAMPLE 10

[0264]

[0265] A. Preparation of Amino Carbamate Resin.

[0266] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added trans-1,4-bisaminocyclohexane (4.57 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0267] B. Coupling of Bromoacetic Acid.

[0268] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0269] C. Preparation of the Secondary Amine

[0270] (Displacement of Bromide by 2-(2-methoxy)phenethylamine)

[0271] The 2-bromoacetylated resin (from B) was swelled in DMSO (approximately 150 ml). To the suspension was added 2-(2-methoxy)phenethylamine (6.045 g, 40 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0272] D. Preparation of Bromophenylsulfonamide Resin

[0273] The resin-bound secondary amine (from C) was swelled in DCM (approximately 200 ml). To the suspension was added pyridine (3.19 g) followed by 4-bromophenylsulfonylchloride (5.1 g, 20 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0274] E. Preparation of Sulfonamide Resin

[0275] The 4-bromophenylsolfonamide resin (from D) was split into 30 portions, each containing 0.133 millimoles of resin. To one portion was added 2-methylbenzeneboronic acid (0.054 g, 0.399 millimoles). To the solution was then added palladium tetrakistriphenylphosphine (0.0154 g, 0.133 millimoles), DME (2.5 ml) and 2M sodium carbonate solution in water (0.830 ml). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0276] F. Cleavage of the Resin Support

[0277] The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0278] Compounds 74-93 and 95-113 were prepared according to the procedure above with appropriate selection and substitution 2-methoxyphenethylamine or 2-methoxybenzylamine in Step C above and appropriate selection and substitution of a suitably substituted boronic acid in Step E above.

EXAMPLE 11

[0279]

[0280] A. Preparation of Amino Carbamate Resin

[0281] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,3-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0282] B. Coupling of Bromoacetic Acid

[0283] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0284] C. Preparation of the Secondary Amine on Resin

[0285] The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added 2-methoxyphenethylamine (5.226 mL, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0286] D. Preparation of 4-Bromophenylsulfonamide Resin

[0287] The resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) followed by 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0288] E. Preparation of Substituted Phenylsulfonamide Resin

[0289] The 4-bromophenylsulfonamide resin (from D) was split into 23 portions, each containing 0.174 millimole of resin. To one portion was added 2-methylbenzeneboronic acid (0.071 g, 0.522 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.020, 0.0174 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (1.086 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0290] F. Cleavage of the Resin Support

[0291] The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0292] Compounds 345-351 were prepared according to the procedure above with appropriate selection and substitution of methoxybenzylamine or methoxyphenethylamine in Step C above and appropriate selection and substitution of a suitably substituted benzeneboronic acid in Step E above.

EXAMPLE 12

[0293]

[0294] A. Preparation of Amino Carbamate Resin

[0295] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,3-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0296] B. Coupling of Bromoacetic Acid

[0297] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0298] C. Preparation of the Optically Pure Secondary Amine on Resin

[0299] The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added (R)-β-methylphenethylamine (5.408 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0300] D. Preparation of 4-Bromophenylsulfonamide Resin

[0301] The optically pure resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0302] E. Preparation of Sulfonamide Resin

[0303] The N-(R)-β-methylphenthyl-4-bromophenyl-sulfonamide resin (from D) was split into 10 portions, each containing 0.133 millimole of resin. To one portion was 3-fluorobenzeneboronic acid (0.056 g, 0.399 millimoles). To the solution was then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0304] F. Cleavage of the Resin Support

[0305] The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0306] Compounds 390, 391, 393, 394 and 395 were prepared according to the procedure above with appropriate selection and substitution of a suitably substituted boronic acid in Step E.

EXAMPLE 13

[0307]

[0308] A. Preparation of Amino Carbamate Resin

[0309] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,3-bisaminomethylcyclohexane (5.69 g, 40 mmol) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0310] B. Coupling of Bromoacetic Acid

[0311] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0312] C. Preparation of the Secondary Amine on Resin

[0313] The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added 2-methoxybenzylamine (5.226 mL, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0314] D. Preparation of 4-Bromophenylsulfonamide Resin

[0315] The resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) followed by 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0316] E. Preparation of Substituted Phenylsulfonamide Resin

[0317] The 4-bromophenylsulfonamide resin (from D) was split into 23 portions, each containing 0.174 millimole of resin. To one portion was added 2-methylbenzeneboronic acid (0.071 g, 0.522 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.020, 0.0174 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (1.086 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0318] F. Cleavage of the Resin Support

[0319] The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0320] Compounds 337-343 were similarly prepared according to the procedure above with suitable selection and substitution of a suitably substituted benzeneboronic acid in Step E.

EXAMPLE 14

[0321]

[0322] A. Preparation of Amino Carbamate Resin

[0323] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,3-bisaminomethylcyclohexane (5.69 g, 40 mmol) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0324] B. Coupling of Bromoacetic Acid

[0325] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0326] C. Preparation of the Optically Pure Secondary Amine on Resin

[0327] The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added (R)-β-methylphenethylamine (5.408 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0328] D. Preparation of 4-Bromophenylsulfonamide Resin

[0329] The optically pure resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0330] E. Preparation of Substituted Phenylsulfonamide Resin

[0331] The N-(R)-β-methylphenethyl-4-bromophenyl-sulfonamide resin (from D) was split into 10 portions, each containing 0.133 millimole of resin. To one portion was 2-methylbenzeneboronic acid (0.054 g, 0.399 mmol). To the solution was then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0332] F. Cleavage of the Resin Support

[0333] The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0334] Compounds 385-389 were similarly prepared according to the procedure above, by appropriate selection of optically pure methylphenethylamine in Step C above, and appropriate selection and substitution of a suitably substituted boronic acid in Step E.

EXAMPLE 15

[0335]

[0336] A. Preparation of Amino Carbamate Resin

[0337] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 15-pentanediamine (4.09 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0338] B. Coupling of Bromoacetic Acid

[0339] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.539) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0340] C. Preparation of the Optically Pure Secondary Amine on Resin

[0341] The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added (R)-β-methylphenethylamine (5.408 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0342] D. Preparation of 4-Bromophenylsulfonamide Resin

[0343] The optically pure resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0344] E. Preparation of Sulfonamide Resin

[0345] The N-(R)-β-methylphenthyl-4-bromophenyl-sulfonamide resin (from D) was split into 10 portions, each containing 0.133 millimole of resin. To one portion was 2-chlorobenzeneboronic acid (0.076 g, 0.399 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0346] F. Cleavage of the Resin Support

[0347] The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0348] Compounds 352, 378 and 380-383 were prepared according to the procedure above with appropriate selection and substitution of substituted benzeneboronic acid in Step E.

[0349] Compounds 353-359 and 396401 were similarly prepared according to the procedure above with substitution of 1,6-n-hexyl diamine for the 1,5-n-pentyl diamine in step B and appropriate selection and substitution of suitably substituted benzeneboronic acid in Step E.

EXAMPLE 16

[0350]

[0351] A. Preparation of Piperazino Carbamate Resin

[0352] Wang p-nitrophenylcarbonate resin (4.0 millimole) was swelled in DMF (200 mL). To the suspension was added piperazine (3.446 g, 40.0 millimole) dissolved in DMF (75 mL). The mixture was shaken for 24 hours. The solvent was removed by filtration. The resin was washed with 3 portions of DMF, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0353] B. Coupling of Bromoacetic Acid

[0354] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0355] C. Preparation of the Secondary Amine on Resin

[0356] The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added 2-methoxybenzylamine (5.226 mL, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0357] D. Preparation of 4-Bromophenylsulfonamide Resin

[0358] The resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) followed by 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0359] E. Preparation of Substituted Phenylsulfonamide Resin

[0360] The 4-bromophenylsulfonamide resin (from D) was split into 23 portions, each containing 0.174 millimole of resin. To one portion was added 2-methylbenzeneboronic acid (0.071 g, 0.522 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.020, 0.0174 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (1.086 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0361] F. Cleavage of the Resin Support

[0362] The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0363] Compounds 152-173 were prepared according to the procedure above with appropriate selection and substitution of substituted boronic acid in step E.

EXAMPLE 17

[0364]

[0365] A. Preparation of Piperazino Carbamate Resin

[0366] Wang p-nitrophenylcarbonate resin (4.0 millimole) was swelled in DMF (200 mL). To the suspension was added piperazine (3.446 g, 40.0 millimole) dissolved in DMF (75 mL). The mixture was shaken for 24 hours. The solvent was removed by filtration. The resin was washed with 3 portions of DMF, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0367] B. Coupling of Bromoacetic Acid

[0368] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0369] C. Preparation of the Secondary Amine on Resin

[0370] The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added 2-methoxybenzylamine (5.226 mL, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0371] D. Preparation of 4-Bromophenylsulfonamide Resin

[0372] The resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) followed by 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0373] E. Preparation of Substituted Phenylsulfonamide Resin

[0374] The 4-bromophenylsulfonamide resin (from D) was split into 23 portions, each containing 0.174 millimole of resin. To one portion was added 2-methylbenzeneboronic acid (0.071 g, 0.522 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.020, 0.0174 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (1.086 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0375] F. Cleavage of the Resin Support

[0376] The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0377] Compounds 175-196 were prepared according to the procedure above with appropriate selection and substitution of substituted boronic acid in step E.

EXAMPLE 18

[0378]

[0379] A. Preparation of Bipiperidino Resin

[0380] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 4,4′-bipiperdine (6.73 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0381] B. Coupling of Bromoacetic Acid

[0382] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0383] C. Preparation of the Optically Pure Secondary Amine on Resin

[0384] The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added (R)-β-methylphenethylamine (5.408 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0385] D. Preparation of 4-Bromophenylsulfonamide Resin

[0386] The optically pure resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0387] E. Preparation of Sulfonamide Resin

[0388] The N-(R)-β-methylphenthyl-4-bromophenyl-sulfonamide resin (from D) was split into 10 portions, each containing 0.133 millimole of resin. To one portion was 2-chlorobenzeneboronic acid (0.076 g, 0.399 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.015, 0.0133 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0389] F. Cleavage of the Resin Support

[0390] The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0391] Compounds 366 and 368-371 were prepared according to the procedure above with appropriate selection and substitution optically pure methylphenethylamine in Step C and appropriate selection and substitution of a suitably substituted benzeneboronic acid in Step E.

EXAMPLE 19

[0392]

[0393] A. Preparation of Amino Carbamate Resin

[0394] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0395] B. Coupling of Bromoacetic Acid

[0396] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol,-and 3 portions DCM.

[0397] C. Preparation of the Secondary Amine on Resin

[0398] The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added 1-amino-2-phenyl-cyclopropane (5.33 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0399] D. Preparation of 4-Bromophenylsulfonamide Resin

[0400] The optically pure resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0401] E. Preparation of Sulfonamide Resin

[0402] The 4-bromophenyl-sulfonamide resin (from D) was split into 10 portions, each containing 0.133 millimole of resin. To one portion was 2-methylbenzeneboronic acid (0.076 g, 0.399 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0403] F. Cleavage of the Resin Support

[0404] The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0405] Compounds 321 and 322 were prepared according to the above procedure with appropriate selection and substitution of a suitably substituted benzeneboronic acid in Step E.

EXAMPLE 20

[0406]

[0407] A. Preparation of Amino Carbamate Resin.

[0408] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0409] B. Coupling of Bromoacetic Acid.

[0410] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0411] C. Preparation of the Secondary Amine

[0412] (Displacement of Bromide by 2-methoxybenzylamine)

[0413] The 2-bromoacetylated resin (from B) was swelled in DMSO (approximately 150 ml). To the suspension was added 3,4-methylenedioxy-benzylamine (6.05 g, 40 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0414] D. Preparation of Sulfonamide Resin

[0415] The resin bound secondary amine (from C) was split into 36 portions each containing 0.111 millimole of resin. One portion was swelled in DCM (1.5 ml). To the suspension was added pyridine (0.089 g), followed by 8-quinolinylsulfonyl chloride (9.70 g, 0.556 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0416] E. Cleavage of the Resin Support

[0417] The product was cleaved from the resin using a cleaving cocktail solution of 90:10 TFA:water. The cleavage solution was evaporated. The product was purified by semi-preparative reversed phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product wa lyophilized and analyzed by ES/MS and reversed phase HPLC.

[0418] Compounds 403, 408, 409 and 411 were prepared according the above procedure with appropriate selection and substitution of a suitable diamine in

[0419] Step A.

EXAMPLE 21

[0420]

[0421] A. Preparation of Amino Carbamate Resin.

[0422] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0423] B. Coupling of Bromoacetic Acid.

[0424] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0425] C. Preparation of the Secondary Amine

[0426] (Displacement of Bromide by 2-methoxybenzylamine)

[0427] The 2-bromoacetylated resin (from B) was swelled in DMSO (approximately 150 ml). To the suspension was added 2-methoxybenzylamine (5.226 mL g, 40 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0428] D. Preparation of Sulfonamide Resin

[0429] The resin bound secondary amine (from C) was split into 36 portions each containing 0.111 millimole of resin. One portion was swelled in DCM (1.5 ml). To the suspension was added pyridine (0.089 g), followed by 2,3-dichlorobenzene sulfonyl chloride (0.137 g, 0.556 millimoles) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0430] E. Cleavage of the Resin Support

[0431] The product was cleaved from the resin using a cleaving cocktail solution of 90:10 TFA:water. The cleavage solution was evaporated. The product was purified by semi-preparative reversed phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product wa lyophilized and analyzed by ES/MS and reversed phase HPLC.

[0432] Compounds 402, 406, 407 and 410 were prepared according the above procedure with appropriate selection and substitution of a suitable diamine in

[0433] Step A.

Example 22

[0434]

[0435] A. Dimethylation of Compound #198.

[0436] Compound #198, prepared as in Example 1 (100 mg, 0.178 millimoles) was dissolved in an equal mixture of TMOF and DCE (3.0 mL). To the solution were then added formaldehyde (16 mg, 0.534 millimoles), NaBH₃CN (34 mg, 0.534 millimoles), and acetic acid (451L, 1.5%). The mixture was stirred for 16 h, and then the reaction was stopped by adding water. The crude product was extracted with chloroform, and the solvent removed under vacuum, to yield the product.

[0437] B. Purification of Product.

[0438] The crude product prepared in Step A was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES⁺/MS and reverse phase HPLC.

[0439] Compounds 472, 474, 475 were similarly prepared according to the procedure above with appropriate selection and substitution of reagents (Compound 472 was prepared by replacing the formaldehyde in Step A with acetaldehyde; Compound 474 was prepared by replacing compound 198 in Step A with compound 215; and Compound 475 by substituting compound 198 and formaldehde were in Step A with compound 215 and acetaldehyde, respectively).

Example 23

[0440]

[0441] A. Acetylation of Compound #198.

[0442] Compound #198, prepared as in Example 1, (100 mg, 0.178 millimoles) was dissolved in chloroform (3.0 mL). To the solution were added acetyl chloride (1945 μL, 0.267 millimoles), and TEA (3745 μL, 0.267 millimoles), and the mixture stirred for 16. The reaction was then stopped by adding water. The crude product was washed twice by 10% NaHCO₃ aqueous solution.

[0443] B. Purification of Product.

[0444] The crude product from Step A was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES⁺/MS and reverse phase HPLC.

[0445] Compound 476 was similarly prepared according to the procedure above, with substitution of compound 198 in Step A with compound 215.

Example 24

[0446]

[0447] A. Preparation of Amino Carbamate Resin

[0448] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 4,4-methylenebis(cyclohexanamine) (8.41 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0449] B. Coupling of Bromoacetic Acid

[0450] The carbamate resin (from Step A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and the mixture shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0451] C. Preparation of the Optically Pure Secondary Amine on Resin

[0452] The 2-bromoacetylated resin (from Step B) was swelled in DMSO (150 mL). To the suspension was added (R)-β-methylphenethylamine (5.408 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0453] D. Preparation of 4-Bromophenylsulfonamide Resin

[0454] The optically pure resin-bound secondary amine resin (from Step C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0455] E. Preparation of Sulfonamide Resin

[0456] The N-(R)-β-methylphenthyl-4-bromophenyl-sulfonamide resin (from Step D) was split into 10 portions, each containing 0.133 millimole of resin. To one portion was added 2-chlorobenzeneboronic acid (0.076 g, 0.399 millimole). To the solution were then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0457] F. Cleavage of the Resin Support

[0458] The product from Step E was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The-product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0459] Compounds 498 through 501 were similarly prepared according to the procedure above with appropriate selection and substitution the desired optically pure phenethylamine in Step C and appropriate selection and substitution of suitably substituted benzeneboronic acid in Step E.

EXAMPLE 25

[0460]

[0461] A. Preparation of Amino Carbamate Resin

[0462] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,6-hexanediamine, (4.65 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0463] B. Coupling of Bromoacetic Acid

[0464] The carbamate resin (from Step A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0465] C. Preparation of the Secondary Amine on Resin

[0466] The 2-bromoacetylated resin (from Step B) was swelled in DMSO (150 mL). To the suspension was added 4-methoxyphenethylamine (6.05 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0467] D. Preparation of 4-Bromophenylsulfonamide Resin

[0468] The optically pure resin-bound secondary amine resin (from Step C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0469] E. Preparation of Sulfonamide Resin

[0470] The N-(R)-β-methylphenthyl-4-bromophenyl-sulfonamide resin (from Step D) was split into 10 portions, each containing 0.133 millimole of resin. To one portion was added 2-chlorobenzeneboronic acid (0.076 g, 0.399 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0471] F. Cleavage of the Resin Support

[0472] The product from Step E was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0473] Compounds 501 through 515 and 572 through 589 may be similarly prepared according to the procedure above with suitably substituted phenethylamines in Step C.

EXAMPLE 26

[0474]

[0475] A. Preparation of Amino Carbamate Resin

[0476] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 1,4-xylenediamine (5.44 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0477] B. Coupling of Bromoacetic Acid

[0478] The carbamate resin (from Step A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0479] C. Preparation of the Optically Pure Secondary Amine on Resin

[0480] The 2-bromoacetylated resin (from Step B) was swelled in DMSO (150 mL). To the suspension was added (R)-β-methylphenethylamine (5.408 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0481] D. Preparation of 4-Biphenylurea Resin

[0482] The optically pure resin-bound secondary amine resin from Step C (0.150 mmol) was swelled in DCE (2.0 mL). To the suspension was added 4-biphenylisocyanate (0.146 g, 0.750 mmol). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0483] E. Cleavage of the Resin Support

[0484] The product from Step D was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0485] Compound #591 was similarly prepared according to the procedure described above with appropriate substitution of (S)-β-methylphenethylamine in Step C.

Example 27

[0486]

[0487] A. Preparation of Amino Carbamate Resin

[0488] Wang p-nitrophenylcarbonate resin (4.0 millimoles) was swelled in DMF (approximately 200 ml). To the suspension was added 4,4-methylenebis(cyclohexanamine) (8.41 g, 40 millimoles) dissolved in DMF (75 ml). The mixture was shaken for 24 h. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, 3 portions DCM/5% acetic acid, 3 portions methanol, 3 portions DCM/10% TEA, and 3 portions methanol. The resin was dried in vacuo overnight.

[0489] B. Coupling of Bromoacetic Acid

[0490] The carbamate resin (from A) was swelled in DMF (approximately 200 ml). To the suspension was added bromoacetic acid (2.77 g, 20 millimoles) and diisopropylcarbodiimide (2.53 g) and shaken overnight. The solvent was removed by filtration. The resin was then washed with 3 portions DMF, 3 portions methanol, and 3 portions DCM.

[0491] C. Preparation of the Optically Pure Secondary Amine on Resin

[0492] The 2-bromoacetylated resin (from B) was swelled in DMSO (150 mL). To the suspension was added (R)-β-methylphenethylamine (5.408 g, 40.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DMSO, 3 portions of methanol, 3 portions of DCM/5% acetic acid, 3 portions of methanol, 3 portions of DCM/10% TEA, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0493] D. Preparation of 4-Iodobenzamide Resin

[0494] The optically pure resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-iodobenzoyl chloride (5.3 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.

[0495] E. Preparation of Sulfonamide Resin

[0496] Five portions of the N-(R)-β-methylphenthyl-4-iodobenzamide resin (from D), each containing 0.133 millimole of resin, were used for the next reaction. To one portion was added 2-chlorobenzeneboronic acid (0.076 g, 0.399 millimole). To the solution was then added palladium tetrakistriphenylphosphine (0.0154, 0.0133 millimole), DME (2.5 mL) and 2 M sodium carbonate solution in water (0.830 mL). The mixture was shaken at 80° C. overnight. The resin was filtered and washed with 3 portions DMF, 3 portions methanol and 3 portions DCM. The resin was dried in vacuo overnight.

[0497] F. Cleavage of the Resin Support

[0498] The product was cleaved from the resin with a solution of 90:10 TFA/water. The cleavage solution was evaporated. The product was purified by semi-preparative reverse phase HPLC on a 20×100 mm J'sphere H-80 YMC column using a gradient of 90:10:0.1 water:acetonitrile:TFA to 10:90:0.1 water:acetonitrile:TFA. The product was lyophillized and analyzed by ES/MS and reverse phase HPLC.

[0499] Compounds 478-481 were similarly prepared according to the procedure above, with appropriate selection and substitution of suitably substituted benzeneboronic acid in Step E.

EXAMPLE 28 IN VITRO TESTING: hFSH-R CHO Cells Preparation of Biological Materials

[0500] Minimum Essential Medium-Alpha (MEM-alpha), fetal bovine serum (FBS), penicillin, streptomycin, geneticin, trypsin-EDTA, Hanks' Balanced Salt Solution (no Calcium chloride, Magnesium chloride, Magnesium sulfate, or phenol red; Ca-Mg free HBSS) were purchased from Gibco BRL (Gaithersburg, Md.). The cells used for the FSH bioassay (rhFSHR-cLUC) were Chinese Hamster Ovary cells (K-1; ATCC) stably transformed with human FSH receptor (pSVK-FSHr) and a cAMP luciferase reporter gene (responsive CGα-180LUC). Follicle Stimulating Hormone (Metrodin; Fertinex) was purchased from Serono, Ltd. (Norwell, Mass.).

[0501] The rhFSHR-cLUC cell cultures were maintained in MEM-Alpha supplemented with 10% heat-inactivated FBS (HIFBS), 100 U/ml penicillin, 100 μg/mL streptomycin, and included 0.1 g/L geneticin for stable cell selection.

HFSHR Assay Procedure

[0502] Forty-eight hours after the cells were plated in sterile 96-well culture plates (Corning, Corning, N.Y.) the spent media was removed and 50 μl assay media (modified growth media with 2% HIFBS) containing 2 mM IBMX (3-isobutyl-1-methyl-xanthine) was added to the cells. Compounds (25 μl) in the appropriate concentration were added followed 5 minutes later by an EC₇₀ dose of FSH (25 μl; 160 ng/ml; 4.85 nM). After 10 minutes @ 22.5° C. (room temperature) the reaction was terminated by addition of 25 μL 0.5 N hydrochloric acid to each well. The amount of cAMP produced was measured by radioimmunoassay in a FlashPlate (DuPont, Boston, Mass.). To each flash plate 60 μL flash plate buffer was added followed by 401L acidified cell sample or cAMP standard, followed with the addition of 1.00 μl ¹²⁵I-cAMP trace. The FlashPlates were sealed, incubated overnight @ room temperature, and counted in a Packard TopCount (Packard Instrument Co., Meriden, Conn.). The cAMP radioimmunoassay results were calculated using DPM conversion and log-logit transformation of % binding (Excel program).

Preparation of Test Compound

[0503] Test compounds were solubilized in 30% dimethyl sulfoxide (DMSO) at a concentration of 10 mM before diluting to appropriate concentrations in assay medium. The final DMSO concentration in the treated cells and in the control cells was 0.75%. The compounds were tested in the assay at a maximum final concentration of 50 μM (primary assay) and compounds that demonstrated greater than 50% inhibition or greater than 200% stimulation of cAMP production were retested in dose-ranging experiments to calculate an EC₅₀.

Derivation and Analysis of Data

[0504] For individual experiments, a set of samples were tested including a vehicle control (assay buffer), a reference compound (hFSH) at a range of concentrations designed to elicit a minimal to maximal response, and several concentrations of test compounds together with an EC₇₀ concentration of standard (hFSH challenge). Each compound was performed in duplicates for the primary evaluation and quadruplicates for the dose-ranging experiments. The cAMP radioimmunoassay raw data (pmol) were calculated to provide average pmol cAMP produced/ml and the percent inhibition was calculated as shown below.

% Inh=[1−(Avg. pmol _(testcompound+standard))/(Avg. pmol standard)]×100

[0505] EC₅₀ values were calculated from an analysis of the concentration-inhibition data using a linear analysis of the data transformed to a log-logit format. TABLE 5 EC₅₀ hFSHR EC₅₀ hFSHR Cmpd # CHO cAMP (μM) Cmpd # CHO-cAMP (μM) 1 1.16 278 1.09 2 0.93 279 2.45 3 0.6 280 7.63 4 0.65 281 6.95 5 0.96 282 9.4 6 1.59 283 1.27 7 1.81 284 3.51 8 1.38 285 7.89 9 1.06 286 3.88 10 3.71 287 7.52 11 0.63 288 19.51 12 0.68 289 5.68 13 0.56 290 0.67 14 0.74 291 8.94 15 0.84 292 0.68 16 1.13 293 7.36 17 0.57 294 1.54 18 1.82 295 2.18 19 3.37 296 50 20 6.31 297 6.88 21 3.29 298 34.38 22 5.03 299 2.22 23 1.41 300 3.18 24 2.33 301 0.15 25 1.41 302 0.2 26 1.46 303 0.44 27 2.3 304 0.3 28 2.23 305 0.58 29 3.09 306 0.35 30 1.33 307 0.19 31 0.91 308 0.45 32 0.31 309 0.34 33 0.42 310 0.22 34 0.31 311 0.05 35 0.83 312 0.22 36 0.66 313 0.43 37 0.67 314 0.69 38 0.5 315 0.31 39 1.69 316 0.96 40 22.13 317 16.92 41 12.69 318 16.97 42 6.46 319 1.1 43 9.88 320 2.57 44 8.92 321 11.3 45 3.92 322 4.36 46 28.85 323 0.29 47 4.37 324 0.37 48 3.62 325 16.96 49 31.3 336 0.98 50 26.24 337 0.31 51 25 338 0.44 52 28.49 339 1.1 53 29.02 340 0.65 54 33.45 341 0.57 55 50 342 0.37 56 23.32 343 0.53 57 19.52 344 0.7 58 6.24 345 18.22 59 28.48 346 0.65 60 40.02 347 0.9 61 50 348 2.24 62 6.76 349 0.79 63 33.61 350 17.47 64 38.47 351 3.15 65 4.82 352 0.11 66 12.67 353 0.14 67 50 354 0.37 68 37.66 355 0.4 69 5.99 356 0.89 70 18.78 357 0.3 71 11 358 1.04 72 7.85 359 0.36 73 4.95 366 0.78 74 10.68 367 1.02 75 5.09 368 1.08 76 10.21 369 0.75 77 6.86 370 0.57 78 12.87 371 1.84 79 7.83 372 0.19 80 3.06 373 0.11 81 7.06 374 0.34 82 5.09 375 0.13 83 4.5 376 0.17 84 50 377 0.34 85 7.79 378 0.25 86 12.34 379 50 87 7.4 380 1.2 88 12.2 381 0.45 89 50 382 0.61 90 50 383 2.9 91 13.19 384 0.27 92 50 385 0.33 93 15.22 386 1.17 94 34.45 387 1.07 95 5.98 388 0.9 96 8.23 389 1.93 97 4.31 390 0.23 98 6.04 391 0.31 99 3.68 392 0.26 100 4.99 393 0.09 101 4.89 394 0.72 102 3.98 395 2.64 103 28.32 396 0.09 104 9.54 397 0.05 105 31.33 398 0.22 106 12.77 399 0.23 107 9.7 400 0.16 108 5.5 401 1.36 109 4.76 402 5.36 110 10.75 412 0.32 111 8.39 413 0.08 112 10.21 414 0.35 113 16.69 415 0.72 114 9.78 416 0.51 115 2.92 417 0.44 116 8.41 418 0.85 117 3.63 419 2.07 118 1.24 420 0.64, 0.21 119 0.54 421 0.55 120 1.5 422 0.52 121 33.11 423 1.38 122 0.76 424 18.85 123 4.03 425 0.42 124 1.11 426 0.7 125 7.53 427 4.75 126 2.31 428 >50 127 10.36 429 3.03, 0.77 128 4.98 430 >50 129 2.11 431 5.98 130 1.86 432 >50 131 1.41 433 23.5 132 2.58 434 0.2 133 50 435 0.21 134 3.86 436 50 135 1.02 437 32.5 136 2.13 438 0.73 137 4.32 439 >50 138 31.21 440 0.9 139 5.76 441 0.12 140 18.57 442 >50 141 50 443 0.85 142 50 444 1.89 143 5 445 1.54 144 1.08 446 >50 145 24.26 447 >50 146 1.73 448 >50 147 8.06 449 0.64 148 23.5 450 0.21 149 1.01 451 0.29, 0.52 150 4.53 452 0.58 151 9.79 453 0.37 152 8.58 454 0.86 153 9.44 455 0.23 154 10.68 456 3.35 155 12.64 457 0.58 156 20.37 458 20.9 157 10.27 459 9.05 158 8.34 460 0.17 159 4.54 461 16.3 160 28.53 462 1.22 161 37.9 463 2.14, 0.58 162 11.24 464 0.73 163 24.27 465 2.19 164 13.8 466 1 165 12.46 467 0.07 166 9.09 468 0.51 167 3.48 469 20.01 168 24.84 470 50 169 8.96 471 49.95 170 8.66 472 >50 171 8.99 473 >50 172 3.76 474 >50 173 2.23 475 9.46 174 50 476 50 175 47.77 477 7.7 176 40.59 478 >50 177 50 479 13.25 178 50 480 0.62 179 50 481 0.67 180 50 483 0.46 181 50 484 0.14 182 50 485 0.11 183 50 486 2.33 184 50 487 0.11 185 50 488 0.22 186 38.9 489 0.35 187 50 490 0.59 188 50 491 0.11 189 50 492 1.08 190 38.23 493 0.99 191 50 494 0.45 192 32.3 495 0.62 193 50 496 0.13 194 50 497 4.04 195 50 498 1.33 196 50 499 3.46 197 0.36 500 2.55 198 0.04 501 0.79 199 0.83 502 0.3 200 0.32 503 0.39 201 0.41 504 >50 202 0.21 505 0.14 203 0.08 506 1.2 204 0.54 507 0.08 205 0.22 508 0.28 206 0.35 509 0.2 207 0.35 510 1.02 208 0.06 511 0.09 209 0.77 512 1.37 210 0.23 513 0.62 211 0.49 514 0.41 212 0.16 515 3.18 213 0.07 521 0.12 214 0.15 522 0.41 215 0.08 523 0.37 216 0.62 524 0.21 217 1.2 525 0.76 218 1.2 526 2.36 219 1.77 527 0.15 220 2.1 528 0.61 221 5.86 529 0.72 222 13.52 530 20 223 6.51 531 >50 224 9.81 532 21.9 225 12.8 533 0.92 226 5.5 534 1 227 5.5 535 4.77 228 3.65 536 >50 229 3.76 537 0.29 230 31.12 538 0.12 231 5.82 539 4.62 232 4.46 540 50 233 8.9 541 0.21 234 27.85 542 0.1 235 8.66 543 0.77 236 3.13 544 0.82 237 50 545 0.19 238 10.49 546 14.8 239 7.99 547 2.5 240 6.83 548 0.23 241 7.45 549 0.29 242 3.51 550 0.36 243 5.17 551 1.27 244 2.88 552 4.2 245 5.63 553 1 246 4.11 554 0.24 247 6.27 555 1.93 248 5.33 556 0.87 249 6.86 557 0.42 250 17.11 558 0.41 251 5.85 559 0.74 252 8.27 560 0.84 253 8.43 561 0.13 254 4.33 562 3 255 2.63 563 1.38 256 2.39 564 0.87 257 1.64 572 0.13 258 2.44 573 0.04 259 2.98 574 0.21 260 3.93 575 0.87 261 5.65 576 0.1 262 2.46 577 0.14 263 31.99 578 50 264 5.62 579 5.29 265 2.69 580 0.35 266 3.43 581 0.1 267 2.08 582 0.43 268 50 583 1.94 269 6.76 584 0.11 270 4.19 585 >50 271 0.96 586 1.24 272 0.55 587 0.29 273 1.16 588 1.06 274 2.08 589 0.25 275 1.6 590 2.6 276 5.1 591 50 277 31.89

EXAMPLE 29 In Vitro Testing: Rat Granulosa Cells Preparation of Biological Materials

[0506] Insulin, diethylstilbesterol, androstenedione, forskolin and DMSO were purchased from Sigma (St. Louis, Mo.). Fungizone, penicillin/streptomycin, charcoal-treated heat inactivated fetal bovine serum (CT-HI-FBS) and Dulbecco's Modified Eagle Medium:Hams F12 medium containing 15 mM Hepes and L-glutamine (DMEM:F12), were purchased from GIBCO BRL (Grand Island, N.Y.).

[0507] Ovine FSH (NIADDK-oFSH-17; FSH potency=20 NIH-FSH-S1 U/mg; LH contamination=0.04 times NIH-LH-S1) was received from Ogden Bioservices Corporation, Rockville, Md. Human FSH (Fertinex), was purchased from Serono Pharmaceutical (Framingham, Mass.). Human chorionic gonadotropin (hCG) was purchased from Sigma (St Louis, Mo.).

Granulosa Cell Culture

[0508] Immature intact female rats (Wistar-derived strain; 21-23 days old) were implanted with a single pellet (Innovative Research of America, Sarasota, Fla.) containing 2.5 mg diethylstilbesterol (DES) for 3 days. On the third day, the animals were sacrificed, the ovaries were removed, and the granulosa cells were isolated essentially as described in Haynes-Johnson et al., Biol. Reprod., 61 (1), 147-153, (1999). Granulosa cells were plated at a density of 300,000 cells per ml with 0.2 ml added to each well of 96 well culture dishes (Corning, N.Y.). Cultures were incubated at 37° C. in a humidified incubator (95% air, 5% CO₂) overnight (18 hours).

[0509] For determination of LH-stimulated estrogen production, immature female rats, about 28 days of age, were treated with 75 IU pregnant mares serum gonadotropin (PMSG) and sacrificed 48 hours later. The granulosa cells from large follicles (not corpora lutea) were expressed into media following the procedure outlined above. Granulosa cells were plated at a density of 300,000 cells/ml with 0.2 ml of cell suspension added to each well of a 96-well plate.

Test Procedure

[0510] Androstenedione (100,000×) was prepared by dissolving the steroid in 100% ethanol, and was subsequently diluted to a final concentration of 10⁻⁷M containing 0.1% ethanol in assay media. The assay media was serum-free, DES-free, insulin-free media, prepared by adding 5 mL pen-strep, 1.5 mL fungizone and 5 μL androstenedione to 493.5 mL DMEM F-12 media.

[0511] Test compounds were solubilized in 30% dimethyl sulfoxide (DMSO) at a concentration of 10 mM before diluting to appropriate concentrations in assay medium. The final DMSO concentration in the treated cells and in the control cells was 0.75%. The compounds were tested in the assay at a maximum final concentration of 50 μM (primary assay) and compounds that demonstrated greater than 50% inhibition or greater than 200% stimulation of cAMP production were retested in dose-ranging experiments to calculate an EC₅₀.

[0512] Test plates containing the granulosa cells were preincubated for 18 hours at 37° C. with 95% air, 5% CO₂, 100% humidity. The spent media was removed and 50 μl assay media (DMEM:F12) containing 2 mM IBMX (3-isobutyl-1-methyl-xanthine) was added to the cells. Compounds (25 μl) in the appropriate concentration were added followed 5 minutes later by an EC₇₀ dose of FSH (25 μl; 50 ng/ml; 1.4 nM). After 30 minutes @ 22.5° C. (room temperature) the reaction was terminated by addition of 25 μL 0.5 N hydrochloric acid to each well. The amount of cAMP produced was measured by radioimmunoassay in a FlashPlate (DuPont, Boston, Mass.). To each flash plate 60 μL flash plate buffer was added followed by 40 μL acidified cell sample or cAMP standard, followed with the addition of 100 μl ¹²⁵I-cAMP trace. The FlashPlates were sealed, incubated overnight @ room temperature, and counted in a Packard TopCount (Packard Instrument Co., Meriden, Conn.). The cAMP radioimmunoassay results were calculated using DPM conversion and log-logit transformation of % binding (Excel program).

Progesterone and Estradiol Production

[0513] The effects of the FSH antagonist on steroid production from rat granulosa cells was used to confirm that the effects on cAMP production also caused changes in progesterone and estradiol production, the biologically relevant steroids in vivo. Granulosa cells prepared as described above were incubated in the absence or presence of test compounds for intervals between 12 and 48 hours to determine the effects of compound on FSH-stimulated progesterone and estradiol production. At the end of incubation the media was aspirated (using a multichannel pipettor) into corresponding microtiter plates, and were stored at −20° C. until the concentration of estradiol and progesterone were measured by radioimmunoassay.

Radioimmunoassay of Estradiol and Progesterone

[0514] Concentrations of E and P in media from the same culture wells were measured using [¹²⁵I]-progesterone and [¹²⁵I]-estradiol Coat-A-Count radioimmunoassay kits (Diagnostic Products Corp., Los Angeles, Calif.). According to the manufacturers specification sheets, the anti-progesterone antibody cross-reacts 2% with 20a-dihydroprogesterone, 2.4% with 11-deoxycortisol, 1.7% with 11-deoxycorticosterone, and 1.3% with 5b-pregnan-3,20-dione. The cross-reactivity of pregnenolone, 17a-hydroxyprogesterone, and testosterone was less than 0.4%. The assay detection limit was 0.03 ng/ml. The anti-estradiol antibody cross-reacts 10% with estrone, 4.4% with equilenin, 1.8% with estrone glucuronide, 0.3% with estriol, and less than 0.1% with other estrogens and androgens. The assay detection limit was 8 pg/ml. TABLE 6 Rat Granulosa Cell Cmpd # EC₅₀ cAMP (μM) 7 2.42 2 0.34 3 0.21 4 0.29 5 0.27 6 0.29 7 0.83 8 0.31 9 0.47 10 1.39 11 0.40 12 0.28 13 0.48 14 1.56 15 5.55 16 0.51 17 0.49 18 0.36 19 1.67 20 0.64 21 5.30 22 0.85 24 1.07 25 1.33 26 4.30 27 1.01 28 1.81 29 2.06 30 0.49 31 1.97 32 0.16 33 0.18 34 0.17 35 0.20 36 0.49 37 0.28 38 1.07 39 0.52 40 1.92 41 0.26 42 1.45 43 0.88 44 0.72 45 2.85 46 6.37 47 0.55 48 1.08 49 2.06 50 1.20 51 3.01 52 3.50 53 3.52 54 3.22 55 12.48 56 5.16 57 1.92 58 2.15 59 2.07 60 29.35 61 7.51 62 1.27 63 3.70 64 1.46 65 1.07 66 4.58 67 25.68 68 3.89 69 5.86 70 5.01 71 3.21 72 2.19 73 1.45 74 8.23 75 0.20 76 0.94 77 0.44 78 0.57 79 1.60 80 0.23 81 25.23 82 0.12 83 0.12 84 7.66 85 0.35 86 2.64 87 0.19 88 0.14 89 1.88 90 0.90 91 0.40 92 3.08 93 0.17 94 8.91 95 0.32 96 3.09 97 0.55 98 0.43 99 0.59 100 0.32 101 25.08 102 0.17 103 0.55 104 32.88 105 8.00 106 10.22 107 1.90 108 1.45 109 3.16 110 4.89 111 1.32 112 8.63 113 0.60 114 8.97 115 1.02 117 1.16 118 2.47 119 2.95 120 1.63 122 1.53 123 10.00 124 1.01 125 2.80 126 25.11 129 1.29 131 1.35 135 1.44 197 0.06 198 0.02 199 0.06 200 0.05 201 0.15 202 0.15 203 0.06 204 0.19 205 0.05 206 0.91 208 0.04 214 0.05 215 0.01 257 1.65 271 2.80 272 0.60 275 2.15 278 0.47 358 0.11 370 0.22 373 0.11 375 0.08 377 0.09 384 0.08 400 0.03

EXAMPLE 30 In Vivo Testing Inhibition of FSH-Stimulated Ovarian Proliferation

[0515] Twenty-one day old immature female Wistar rats (Charles River) are implanted with Alzet pumps (Alza Corp.,) containing human FSH at a concentration calculated to deliver 4-8IU hFSH per day. The animals are given vehicle or test compound at a dosage level of 20 mg/kg compound (BID) dissolved in hydroxypropyl methylcellulose (HPMC). On the third or fourth day, blood samples are obtained by orbital puncture for the measurement of serum estrogen and progesterone, and immediately afterwards, ovaries and uterus are collected, weighed and prepared for histological examination. The effect of test compound is determined by measuring the weight of ovaries and uterus collected from animals treated with the test compound as compared with the weight of ovaries and uterus collected from animals treated with vehicle.

Interruption of 4-Day Estrus Cycle

[0516] The estrus cycles of mature cycling female Wistar rats (250 g) were monitored for 2 consecutive estrus cycles to select animals with regular 4-day estrus cycles. The animals were randomly assigned to treatment groups on the morning of estrus. Starting on the morning of estrus and continuing through 2 estrus cycles, the animals orally dosed with vehicle or test compound at a concentration of 20 mg/kg; BID. At the end of the second estrus cycle, blood samples were collected by orbital puncture on the morning of estrus. The animals were then sacrificed, and the number of ovulated eggs in the oviduct were counted. TABLE 7 Estradiol Progesterone # Ovulated Cmpd. # Concentration Concentration Eggs 198 20.1 ± 4.4 3.6 ± 0.9 14.0 215 22.2 ± 4.2 2.6 ± 0.6 16.3 Vehicle 23.8 ± 3.1 8.0 ± 2.7 16.3

Effects on Spermatogenesis in Immature Male Rats

[0517] Twenty-one day old immature male Wistar rats (Charles River) were treated with FSH antagonist at a concentration of 20 mg/kg BID for 25 days. On the penultimate day of treatment, blood samples were collected by orbital puncture immediately prior to oral dosing, and 3 hours after dosing into Vacutainers containing EDTA. On the last day of treatment, blood samples were again collected prior to time of compound administration. The concentrations of LH, FSH and testosterone were measured in the plasma. Testosterone was measured using a Coat-A-Count kit (Diagnostic Products Corp.) and luteinizing hormone and follicle stimulating hormone concentrations were measured following previously established. At the end of the treatment period, the animals were sacrificed, testes and prostates were collected and weighed, and the testes were prepared for histological examination. The presence of sperm in testes were evaluated by hematoxylin and eosin staining, and in separate slides with a BERG stain (REF, 1963). TABLE 8 Serum Testosterone Testes Prostate Mating Cmpd. # (t = 3 hr, d = 25) Weight Weight Sperm 198 3.6 ± 0.6 8.8 ± 0.2 1.6 ± 0.2 3/4 215 4.9 ± 0.7 8.7 ± 0.5 1.8 ± 0.1 1/4 

We claim:
 1. A compound of the formula:

wherein R¹ and R² are independently selected from the group consisting of hydrogen, C₁-C₆alkyl, C₁-C₆alkylcarbonyl, C₁-C₆perhaloalkyl, phenyl, phenyl C₁-C₆alkyl-, phenylcarbonyl-, pyridyl, pyridyl C₁-C₆alkyl-, pyridylcabonyl-, thienyl, thienyl C₁-C₆alkyl- and thienylcarbonyl, wherein the phenyl, pyridyl or thienyl is optionally substituted with one to three substituents independently selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy or NO₂; R³ is selected from the group consisting of hydrogen, C₁-C₆alkyl, C₂-C₄alkenyl and C₂-C₄alkynyl, where the C₁-C₆alkyl is optionally substituted with a phenyl, pyridyl, thienyl or furyl, wherein the phenyl, pyridyl, thienyl or furyl is optionally substituted with one to three substituents independently selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy or NO₂; R⁴ is selected from the group consisting of —C₂-C₆alkyl-, -cyclopentyl-, -cylcohexyl-, -cyclohexyl-CH₂—, —CH₂-cyclohexyl-CH₂—, —CH₂-phenyl-CH₂—, —C(O)—CH₂-phenyl-CH₂—, —C(O)—C₁-C₆alkyl- and -cyclohexyl-CH₂-cyclohexyl; where the R⁴ substituent is inserted into the compound of formula (I) from left to right, as defined; alternately, R², R³, and R⁴ can be taken together with the two N atoms of the diamine portion of the molecule to form

 alternately, R³ can be taken together with R² as —C₂-C₃alkyl-, provided that R⁴ is —C₂-C₆alkyl-; L is selected from the group consisting of —C₃-C₆cycloalkyl (wherein the cycloalkyl is substituted with R⁵ and R⁶), a bicyclic compound of the form

 (wherein the point of the attachment of the bicyclic compound is any carbon atom of the alkyl portion and wherein the aromatic portion of the bicyclic compound is optionally substituted with one to three substituents independently selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, NO₂, acetamido, —NH₂, —NH(C₁-C₆alkyl) or —N(C₁-C₆alkyl)₂), and —(CH₂)_(m)—CR⁸R⁵R^(6;) m is 0 to 3; R⁵ is selected from the group consisting of phenyl, naphthyl, (wherein the phenyl and naphthyl may be optionally substituted with one to three substituents independently selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, NO₂, acetamido, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, C₁-C₆alkylcarbonylamino or C₁-C₆alkylsulfonylamino), bicyclo[4.2.0]octa-1,3,5-trienyl, 2,3-dihydro-1H-indolyl, N-methylpyrrolidinyl, 3,4-methylenedioxyphenyl, C₃-C₆cyloalkenyl, (wherein the cycloalkenyl group contains one or two double bonds), a six membered heteroaryl (wherein the six membered heteroaryl contains one to three N atoms), and a five membered heteroaryl (wherein the five membered heteroaryl contains one sulfur, oxygen or nitrogen, optionally contains one to three additional nitrogen atoms); wherein the point of attachment for the five or six membered heteroaryl is a carbon atom; and wherein the five or six membered heteroaryl is optionally substituted with one to three substituents independently selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy or NO₂; R⁶ is selected from the group consisting of hydrogen, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₁-C₆alkoxy, hydroxy and phenyl, (wherein the phenyl may be optionally substituted with one to three substituents independently selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl or trifluoromethoxyl); provided that R⁶ may be phenyl only when R⁵ is phenyl; R⁸ is selected from the group consisting of hydrogen and C₁-C₆alkyl; Z is selected from the group consisting of —SO₂—, —C(═O)—, and —C(═O)NH—; p is 0 to 1;

 X is selected from the group consisting of phenyl, napthyl, quinolinyl, thienyl, and furyl; X is selected from the group consisting of halogen, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, NO₂, acetamido, —NH₂, —NH(C₁-C₆alkyl) and —N(C₁-C₆alkyl)₂; n is 0 to 3; Y is selected from the group consisting of phenyl, —O-phenyl, —NH-phenyl, naphthyl, (wherein the phenyl or naphthyl is optionally substituted with one to three substituents selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, NO₂, cyano, methylthio, acetamido, formyl, -amino, -aminocarbonyl, —NH C₁-C₆alkyl, —N(C₁-C₆alkyl)₂, —COOH, —COO(C₁-C₆alkyl), —COO(C₁-C₆alkylphenyl), C₁-C₆alkylcarbonylamino, C₁-C₆alkylaminocarbonyl, di(C₁-C₆alkyl)aminocarbonyl, aminosulfonyl, C₁-C₆akylaminosulfonyl or di(C₁-C₆alkyl)aminosulfonyl)), biphenyl, 3,4-methylenedioxyphenyl, dianthrenyl, dibenzothienyl, phenoxathiinyl, a six membered heteroaryl (wherein the six membered heteroaryl contains one to three nitrogen atoms), and a five membered heteroaryl (wherein the five membered heteroaryl contains one sulfur, oxygen or nitrogen atom, optionally contains one to three additional nitrogen atoms); wherein the point of attachment for the five or six membered heteroaryl is a carbon atom; and wherein the five or six membered heteroaryl is optionally substituted with one to three substituents selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, formyl, NO₂, cyano, methylthio, acetamido, -amino, -aminocarbonyl, —NH C₁-C₆alkyl, —N(C₁-C₆alkyl)₂, —COOH, —COO(C₁-C₆alkyl), or —COO(C₁-C₆alkylphenyl)); q is 0 to 1; provided that when q is 1, n is 0; and stereoisomers and pharmaceutically acceptable salts or esters thereof.
 2. The compound of claim 1 wherein R¹ and R² are independently selected from the group consisting of hydrogen, methyl, ethyl, methylcarbonyl, trifluoromethyl, phenyl, benzyl, phenylcarbonyl, pyridyl, pyridylcarbonyl, thienyl, thienylmethyl and thienylcarbonyl (where the phenyl, pyridyl or thienyl is optionally substituted with one to two substituents independently selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, trifluoromethyl, trifluoromethoxy or nitro); and R³ is selected from the group consisting of hydrogen, methyl, —CH═CH— (optionally substituted with phenyl, pyridyl or thienyl; wherein the phenyl, pyridyl or thienyl is further optionally substituted with one to two substituents independently selected from the group consisting of halogen, C₁-C₃alkyl, C₁-C₃alkoxy, trifluoromethyl, trifluoromethoxy and nitro), —C≡C—, (optionally substituted with phenyl, pyridyl or thienyl; wherein the phenyl, pyridyl or thienyl is further optionally substituted with one to two substituents independently selected from the group consisting of halogen, C₁-C₃alkyl, C₁-C₃alkoxy, trifluoromethyl, trifluoromethoxy and nitro).
 3. The compound of claim 1 wherein R¹, R², and R³ are the same and are hydrogen.
 4. The compound of claim 1 wherein one of R¹ or R² is other than hydrogen.
 5. The compound of claim 1 wherein R² and R³ are taken together as C₂-C₃alkyl and R⁴ is C₂-C₆alkyl.
 6. The compound of claim 1 wherein R², R³, and R⁴ are taken together with the two N atoms of the diamine portion of the molecule to form


7. The compound of claim 1 wherein R⁴ is selected from the group consisting of —C₂-C₆alkyl, -cyclohexyl, —C H₂-cyclohexyl-CH₂, -cyclohexyl-CH₂-cyclohexyl- and —CH₂-phenyl-CH₂—.
 8. The compound of claim 1 wherein L is selected from the group consisting of -cyclopropyl-, cyclohexyl-, (wherein the cyclopropyl or cyclohexyl is substituted with R⁵ and R⁶),

and (CH₂)_(m)-CR⁸R⁵R⁶.
 9. The compound of claim 1 wherein R⁵ is selected from the group consisting of phenyl (wherein the phenyl is optionally substituted with one to two substituents independently selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, trifluoromethyl, trifluoromethoxy, methylcarbonylamino, methylsulfonylamino, nitro, acetomido, amino, C₁-C₃alkylamino or di(C₁-C₃alkyl)amino), N-methylpyrrolidinyl, 3,4-methylenedioxyphenyl, bicyclo[4.2.0]octa-1,3,5-trienyl, 2,3-dihydro-1H-indolyl, C₃-C₆cycloalkenyl (wherein the cycloalkenyl contains one or two double bonds), thienyl, furyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyrazinyl and triazinyl.
 10. The compound of claim 1 wherein R⁶ is selected from the group consisting of hydrogen, C₁-C₃alkyl, cyclopropyl, cyclobutyl, cyclohexyl, C₁-C₃alkoxy, hydroxy and phenyl (wherein the phenyl is optionally substituted with one to two substituents independently selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, trifluoromethyl or trifluoromethoxy); provided that R⁶ is phenyl only when R⁵ is phenyl.
 11. The compound of claim 1 wherein R⁸ is selected from the group consisting of hydrogen and C₁-C₃alkyl.
 12. The compound of claim 1 wherein

is selected from the group consisting of phenyl, naphthyl, quinolinyl and thienyl.
 13. The compound of claim 1 wherein X is selected from the group consisting of halogen, C₁-C₆alkyl, C₁-C₄alkoxy, trifluoromethyl, trifluoromethoxy, nitro, acetamido, amino, C₁-C₃alkylamino and di(C₁-C₃alkyl)amino.
 14. The compound of claim 1 wherein Y is selected from the group consisting of phenyl, naphthyl (wherein the phenyl or naphthyl is optionally substituted with one to three substituents independently selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, trifluoromethyl, trifluoromethoxy, formyl, nitro, cyano, methylthio, acetamido, amino, aminocarbonyl, C₁-C₃alkylamino, di(C₁-C₃alkyl)amino, carboxy, —COO(C₁-C₃alkyl), —COO(C₁-C₃alkylphenyl), C₁-C₄alkylaminosulfonyl or C₁-C₄alkylcarbonylamino), 3,4-methylenedioxyphenyl, dianthryl, dibenzothienyl, phenoxathiinyl, a five membered heteroaryl (wherein the five membered heteroaryl contains one nitrogen, oxygen or sulfur atom and optionally contains an additional nitrogen or oxygen atom) and a six membered heteroaryl (wherein the six membered heteroaryl contains one nitrogen atom and optionally contains an additional nitrogen or oxygen atom); wherein the five or six membered heteroaryl is optionally substituted with one to two substituents independently selected from halogen, C₁-C₃alkyl, C₁-C₃alkoxy, trifluoromethyl, trifluoromethoxy, formyl, nitro, cyano, methylthio, acetamido, amino, aminocarbonyl, C₁-C₃alkylamino or di(C₁-C₃alkyl)amino; and wherein the point of attachment for the five or six membered heteroaryl is a carbon atom.
 15. The compound of claim 1 of the formula

wherein m, R⁵, R⁶, p, Y and the stereospecifically are selected in concert from the group consisting of: m R⁵ R⁶ Stereo p Y 1 2-methoxyphenyl H — 0 2-methylphenyl 1 2-methoxyphenyl H — 0 2-chlorophenyl 1 2-methoxyphenyl H — 0 2-methoxyphenyl 1 2-methoxyphenyl H — 0 2,4-dichlorophenyl 1 2-methoxyphenyl H — 0 2,4-dichlorophenyl 0 2-methoxyphenyl H — 0 2-methylphenyl 0 2-methoxyphenyl H — 0 2-chlorophenyl 0 2-methoxyphenyl H — 0 2-methoxyphenyl 0 2-methoxyphenyl H — 0 2,4-dichlorophenyl 1 phenyl CH₃ R 0 2-methylphenyl 1 phenyl CH₃ R 0 2-chlorophenyl 1 phenyl CH₃ R 0 3-fluorophenyl 1 phenyl CH₃ S 0 2-methylphenyl 1 phenyl CH₃ S 0 2-chlorophenyl 1 phenyl CH₃ S 0 3-fluorophenyl


16. The compound of claim 1 of the formula

wherein m, R⁵, R⁶, p, Y and the stereospecificity are selected in concert from the group consisting of: m R⁵ R⁶ Stereo p Y 1 2-methoxyphenyl H — 0 2-methylphenyl 1 2-methoxyphenyl H — 0 2-chlorophenyl 1 2-methoxyphenyl H — 0 2-methoxyphenyl 1 2-methoxyphenyl H — 0 2,4-dichlorophenyl 0 2-methoxyphenyl H — 0 2-methyl 0 2-methoxyphenyl H — 0 2-chlorophenyl 0 2-methoxyphenyl H — 0 2-methoxyphenyl 0 2-methoxyphenyl H — 0 2,4-dichlorophenyl 1 phenyl CH₃ R 0 2-methylphenyl 1 phenyl CH₃ R 0 2-chlorophenyl 1 phenyl CH₃ R 0 3-fluorophenyl 1 phenyl CH₃ S 0 2-methylphenyl 1 phenyl CH₃ S 0 2-chlorophenyl 1 phenyl CH₃ S 0 3-fluorophenyl


17. The compound of claim 1 of the formula

wherein m and Y are selected in concert from the group consisting of: m Y 0 2-methylphenyl 0 3-thienyl 0 2-methoxyphenyl 0 4-fluorophenyl 0 2,3-dimethoxyphenyl 0 4-methoxyphenyl 0 4-methylphenyl 0 1-naphthyl 0 2-chlorophenyl 0 3-pyridyl 0 2-thienyl 0 3-aminocarbonylphenyl 0 phenyl 0 4-chlorophenyl 0 4-[3,5-dimethylisoxazolyl] 0 2-furyl 0 4-cyanophenyl 0 4-pyridyl 0 3-methoxyphenyl 0 4-aminophenyl 1 2-methylphenyl 1 3-thienyl 1 2-methoxyphenyl 1 4-fluorophenyl 1 2,3-dimethoxyphenyl 1 4-methoxyphenyl 1 4-methylphenyl 1 1-naphthyl 1 2-chlorophenyl 1 3-pyridyl 1 2-thienyl 1 3-aminocarbonylphenyl 1 phenyl 1 4-chlorophenyl 1 4-[3,4-dimethylisoxazolyl] 1 2-furyl 1 4-cyano phenyl 1 4-pyridyl 1 3-methoxyphenyl 1 4-aminophenyl


18. The compound of claim 1 of the formula

wherein m, R⁵, R⁶ and Y are selected in concert from the group consisting of: m R⁵ R⁶ Y 0 2-methoxyphenyl H 4-chlorophenyl 0 2-methoxyphenyl H 3-trifluoromethylphenyl 0 2-methoxyphenyl H 2-chlorophenyl 0 2-methoxyphenyl H 2-methylphenyl 0 2-methoxyphenyl H 2-methoxyphenyl 0 2-methoxyphenyl H 2,4-dichlorophenyl 0 2-methoxyphenyl H 3,5-di(trifluoromethyl)phenyl 0 2-methoxyphenyl H 3-chloro-4-fluorophenyl 0 2-methoxyphenyl H 4-methoxyphenyl 0 3-methoxyphenyl H 3-trifluoromethylphenyl 0 3-methoxyphenyl H 2-methoxyphenyl 0 3-methoxyphenyl H 2,4-dichlorophenyl 0 3-methoxyphenyl H 3-fluorophenyl 0 3-methoxyphenyl H 3-methoxyphenyl 0 3-methoxyphenyl H 4-methylphenyl 0 3-methoxyphenyl H 4-fluorophenyl 0 3-methoxyphenyl H 3-chloro-4-fluorophenyl 0 3-methoxyphenyl H 4-methoxyphenyl 1 2-methoxyphenyl H 3-trifluoromethyl phenyl 1 2-methoxyphenyl H 3-nitrophenyl 1 2-methoxyphenyl H 2-chlorophenyl 1 2-methoxyphenyl H 2-methylphenyl 1 2-methoxyphenyl H 2-methoxyphenyl 1 2-methoxyphenyl H 2,4-dichlorophenyl 1 2-methoxyphenyl H phenyl 1 2-methoxyphenyl H 3-chlorophenyl 1 2-methoxyphenyl H 4-fluorophenyl 1 2-methoxyphenyl H 2-trifluoromethyl phenyl


19. The compound of claim 1 of the formula

wherein R⁵, R⁶, p,

and X are selected on concert from the group consisting of: R⁵ R⁶ p

X 2-methoxyphenyl H 0 phenyl — 2-methoxyphenyl H 0 2-thienyl 5-chloro 2-methoxyphenyl H 0 1-phenyl 3-trifluoromethyl 2-methoxyphenyl H 0 1-phenyl 2-trifluoromethyl 2-methoxyphenyl H 0 1-phenyl 3-chloro 2-methoxyphenyl H 0 1-phenyl 3,4-dichloro 2-methoxyphenyl H 0 2-naphthyl — 2-methoxyphenyl H 0 1-phenyl 2-chloro 2-methoxyphenyl H 0 1-phenyl 4-chloro 2-methoxyphenyl H 0 3-thienyl 2,5-dichloro 2-methoxyphenyl H 0 1-phenyl 2,4-dichloro 2-methoyxphenyl H 0 1-phenyl 2,6-dichloro 2-methoxyphenyl H 0 1-phenyl 3,5-dichloro 2-methoxyphenyl H 0 1-phenyl 2,5-dichloro 2-methoxyphenyl H 0 1-phenyl 2,3-dichloro 2-methoxyphenyl H 1 phenyl — 2-methoxyphenyl H 0 1-phenyl 4-methyl 2-methoxyphenyl H 0 1-phenyl 4-methoxy 2-methoxyphenyl H 0 1-naphthyl — 2-methoxyphenyl H 0 1-phenyl 4-fluoro 2-methoxyphenyl H 0 1-phenyl 3,4-dimethoxy 2-methoxyphenyl H 0 1-phenyl 2,5-dimethoxy 2-methoxyphenyl H 0 1-phenyl 2-nitro 2-methoxyphenyl H 0 1-phenyl 4-nitro 2-methoxyphenyl H 0 1-phenyl 3-nitro 2-methoxyphenyl H 0 1-phenyl 4-iodo 2-methoyxphenyl H 0 1-phenyl 4-tert-butyl 2-methoxyphenyl H 0 1-phenyl 2-nitro-4-methoxy 2-methoxyphenyl H 0 1-phenyl 3-methyl-4-methoxy 2-methoxyphenyl H 0 1-phenyl 2-nitro-4- trifluoromethyl 2-methoxyphenyl H 0 1-phenyl 3-fluoro 2-methoxyphenyl H 0 1-phenyl 2-fluoro 2-methoxyphenyl H 0 1-phenyl 4-trifluoromethyl 2-methoxyphenyl H 0 1-phenyl 4-trifluoromethoxy 2-methoxyphenyl H 0 1-phenyl 2,3-dichloro 3,4- H 0 8-quinolinyl — methylenedioxyphenyl


20. The compound of claim 1 of the formula

wherein the stereospecifically and Y are selected in concert from the group consisting of: Stereo Y R 2-methylphenyl R 2-chlorophenyl R 3-fluorophenyl S 2-methylphenyl S 2-chlorophenyl S 3-fluorophenyl


21. The compound of claim 1 of the formula

wherein R⁵, R⁶,

Y and stereospecificity are selected in concert from the group consisting of: Ster- R⁵ R⁶ eo

Y 2-methoxyphenyl H — 1,4-phenyl 3-nitrophenyl 2-methoxyphenyl H — 1,4-phenyl 2-chlorophenyl 2-methoxyphenyl H — 1,4-phenyl 2-methylphenyl 2-methoxyphenyl H — 1,4-phenyl 2-methoxy phenyl 2-methoxyphenyl H — 1,4-phenyl 3-fluorophenyl 2-methoxyphenyl H — 1,4-phenyl phenyl 2-methoxyphenyl H — 1,4-phenyl 3-methoxy phenyl 2-methoxyphenyl H — 1,4-phenyl 4-fluorophenyl 2-methoxyphenyl H — 1,4-phenyl 2-trifluoromethylphenyl 2-methoxyphenyl H — 1,4-phenyl 3-chloro-4-fluorophenyl phenyl CH₃ R 1,4-phenyl phenyl phenyl CH₃ S 1,4-phenyl phenyl phenyl CH₃ S 1,4-phenyl 2-chlorophenyl phenyl CH₃ S 1,4-phenyl 3-chlorophenyl phenyl CH₃ S 1,4-phenyl 2-methoxyphenyl phenyl CH₃ S 1,4-phenyl 3-methoxyphenyl phenyl CH₃ S 1,4-phenyl 4-methoxyphenyl phenyl CH₃ S 1,4-phenyl 3-fluorophenyl phenyl CH₃ S 1,4-phenyl 4-fluorophenyl phenyl CH₃ S 1,4-phenyl 2-methylphenyl phenyl CH₃ S 1,4-phenyl 4-methylphenyl 2-methoxyphenyl H — 1,2-phenyl 2-thienyl 2-methoxyphenyl H — 1,2-phenyl 2-methylphenyl 2-methoxyphenyl H — 1,2-phenyl 3-thienyl 2-methoxyphenyl H — 1,2-phenyl 2-methoxyphenyl 2-methoxyphenyl H — 1,2-phenyl 4-fluorophenyl 2-methoxyphenyl H — 1,2-phenyl 4-methoxyphenyl 2-methoxyphenyl H — 1,2-phenyl 4-methylphenyl 2-methoxyphenyl H — 1,2-phenyl 1-naphthyl 2-methoxyphenyl H — 1,2-phenyl 4-chlorophenyl 2-methoxyphenyl H — 1,2-phenyl 3-methoxy phenyl 2-methoxyphenyl H — 1,2-phenyl 3-aminophenyl 2-methoxyphenyl H — 1,2-phenyl 3-fluorophenyl 2-methoxyphenyl H — 1,2-phenyl 2-fluorophenyl 2-methoxyphenyl H — 1,2-phenyl 1-(3,4-methylene dioxyphenyl) 2-methoxyphenyl H — 1,2-phenyl phenyl 2-methoxyphenyl H — 1,2-phenyl 4-(3,5-dimethyl isoxazole) 2-methoxyphenyl H — 1,2-phenyl 4-cyanophenyl 2-methoxyphenyl H — 1,2-phenyl 4-pyridyl 2-methoxyphenyl H — 1,2-phenyl 2,3,4-trimethoxyphenyl 2-methoxyphenyl H — 1,2-phenyl 3-cyanophenyl 2-methoxyphenyl H — 1,2-phenyl 2,5-dimethoxyphenyl 2-methoxyphenyl H — 1,2-phenyl 2,4-dichlorophenyl 2-methoxyphenyl H — 1,2-phenyl 3-trifluoromethylphenyl 2-methoxyphenyl H — 1,2-phenyl 4-trifluoromethylphenyl 2-methoxyphenyl H — 1,2-phenyl 2-trifluoromethylphenyl 2-methoxyphenyl H — 1,2-phenyl 3-methylphenyl 2-methoxyphenyl H — 1,3-phenyl 2-methylphenyl 2-methoxyphenyl H — 1,3-phenyl 3-thienyl 2-methoxyphenyl H — 1,3-phenyl 2-methoxyphenyl 2-methoxyphenyl H — 1,3-phenyl 4-fluorophenyl 2-methoxyphenyl H — 1,3-phenyl 4-methoxyphenyl 2-methoxyphenyl H — 1,3-phenyl 4-methoxyphenyl 2-methoxyphenyl H — 1,3-phenyl 1-naphthyl 2-methoxyphenyl H — 1,3-phenyl 3-pyridyl 2-methoxyphenyl H — 1,3-phenyl 4-chlorophenyl 2-methoxyphenyl H — 1,3-phenyl 3-methoxyphenyl 2-methoxyphenyl H — 1,3-phenyl 3-aminophenyl 2-methoxyphenyl H — 1,3-phenyl 3-fluorophenyl 2-methoxyphenyl H — 1,3-phenyl 2-fluorophenyl 2-methoxyphenyl H — 1,3-phenyl 1-(3,4-methylene dioxyphenyl) 2-methoxyphenyl H — 1,3-phenyl 3-chlorophenyl 2-methoxyphenyl H — 1,3-phenyl phenyl 2-methoxyphenyl H — 1,3-phenyl 4-(3,5-dimethyl isoxazole) 2-methoxyphenyl H — 1,3-phenyl 4-cyanophenyl 2-methoxyphenyl H — 1,3-phenyl 4-pyridyl 2-methoxyphenyl H — 1,3-phenyl 2,3,4-trimethoxyphenyl 2-methoxyphenyl H — 1,3-phenyl 4-cyanophenyl 2-methoxyphenyl H — 1,3-phenyl 2,5-dimethoxyphenyl 2-methoxyphenyl H — 1,3-phenyl 3-trifluoromethylphenyl 2-methoxyphenyl H — 1,3-phenyl 4-trifluoromethylphenyl 2-methoxyphenyl H — 1,3-phenyl 2-trifluoromethylphenyl 2-methoxyphenyl H — 1,3-phenyl 3-methylphenyl 2-methoxyphenyl H — 2,5-thienyl 2-thienyl 2-methoxyphenyl H — 2,5-thienyl 2-methylphenyl 2-methoxyphenyl H — 2,5-thienyl 3-thienyl 2-methoxyphenyl H — 2,5-thienyl 2-methoxyphenyl 2-methoxyphenyl H — 2,5-thienyl 4-fluorophenyl 2-methoxyphenyl H — 2,5-thienyl 4-methoxyphenyl 2-methoxyphenyl H — 2,5-thienyl 4-methylphenyl 2-methoxyphenyl H — 2,5-thienyl 2-chlorophenyl 2-methoxyphenyl H — 2,5-thienyl 3-pyridyl 2-methoxyphenyl H — 2,5-thienyl 4-chlorophenyl 2-methoxyphenyl H — 2,5-thienyl 3-methoxyphenyl 2-methoxyphenyl H — 2,5-thienyl 3-aminophenyl 2-methoxyphenyl H — 2,5-thienyl 3-fluorophenyl 2-methoxyphenyl H — 2,5-thienyl 2-fluorophenyl 2-methoxyphenyl H — 2,5-thienyl 3-chlorophenyl 2-methoxyphenyl H — 2,5-thienyl phenyl 2-methoxyphenyl H — 2,5-thienyl 4-(3,5-dimethyl isoxazole) 2-methoxyphenyl H — 2,5-thienyl 4-cyanophenyl 2-methoxyphenyl H — 2,5-thienyl 4-pyridyl 2-methoxyphenyl H — 2,5-thienyl 2,3,4-trimethoxyphenyl 2-methoxyphenyl H — 2,5-thienyl 3-cyanophenyl 2-methoxyphenyl H — 2,5-thienyl 2-furyl 2-methoxyphenyl H — 2,5-thienyl 2,5-dimethoxyphenyl 2-methoxyphenyl H — 2,5-thienyl 2,4-dichlorophenyl 2-methoxyphenyl H — 2,5-thienyl 3-trifluoromethylphenyl 2-methoxyphenyl H — 2,5-thienyl 4-trifluoromethylphenyl 2-methoxyphenyl H — 2,5-thienyl 2-trifluoromethylphenyl 2-methoxyphenyl H — 2,5-thienyl 3-methylphenyl


22. The compound of claim 1 of the formula

wherein p, m,

and X are selected in concert from the group consisting of: p m

X 0 1 2-thienyl 5-chloro 0 1 phenyl 3-trifluoromethyl 0 1 phenyl 2-trifluoromethyl 0 1 phenyl 3-chloro 0 1 phenyl 3,4-dichloro 0 1 2-naphthyl — 0 1 phenyl 2-chloro 0 1 phenyl 2,5-dimethoxy 0 1 phenyl 2,4-dichloro 0 1 phenyl 2,6-dichloro 0 1 phenyl 2,5-dichloro 0 1 phenyl 3,5-dichloro 0 1 2-thienyl 4,5-dichloro 1 1 phenyl — 0 1 phenyl 4-methoxy 0 1 1-naphthyl — 0 1 phenyl 4-fluoro 0 1 phenyl 3-fluoro 0 1 phenyl 2-fluoro 0 1 phenyl 3,4-dimethoxy 0 1 phenyl 2-nitro 0 1 phenyl 3-nitro 0 1 phenyl 4-nitro 0 1 phenyl 4-iodo 0 1 phenyl 4-t-butyl 0 1 phenyl 2-nitro-4-methoxy 0 1 phenyl 2-methoxy-5-methyl 0 1 2-thienyl 4-nitro-5-chloro 0 1 phenyl 2-nitro-4-trifluoro methyl 0 1 phenyl 4-trifluoromethyl 0 1 phenyl 4-trifluoromethoxy 0 1 2-thienyl — 0 1 phenyl 4-methyl 0 1 phenyl 4-chloro 0 1 phenyl — 0 0 1-phenyl 2,3-dichloro


23. The compound of claim 1 of the formula

wherein R⁵,

and Y are selected on concert from the group consisting of: R⁵

Y 2-methoxyphenyl 2-thienyl 5-(2-methylthio-pyrimidyl) 3,4-methylenedioxyphenyl 8-quinolinyl —


24. The compound of claim 1 of the formula

wherein R⁵, R⁶, Z,

Y and the stereospecificity are selected in concert from the group consisting of: Ster- R⁵ R⁶ eo Z

Y 2-methoxy H — SO₂ 2,5-thienyl 2-pyridyl phenyl 2-methoxy H — SO₂ 2,5-thienyl 5-(2-methylthio- phenyl pyrimidyl) phenyl CH₃ R SO₂ 1,4-phenyl 2-chlorophenyl phenyl CH₃ R SO₂ 1,4-phenyl 3-chlorophenyl phenyl CH₃ R SO₂ 1,4-phenyl 2-methoxyphenyl phenyl CH₃ R SO₂ 1,4-phenyl 3-methoxyphenyl phenyl CH₃ R SO₂ 1,4-phenyl 4-methoxyphenyl phenyl CH₃ R SO₂ 1,4-phenyl 3-fluorophenyl phenyl CH₃ R SO₂ 1,4-phenyl 4-fluorophenyl phenyl CH₃ R SO₂ 1,4-phenyl 2-methylphenyl phenyl CH₃ R SO₂ 1,4-phenyl 4-methylphenyl 2-methoxy H — SO₂ 1,2-phenyl 3-chlorophenyl phenyl 2-methoxy H — SO₂ 1,3-phenyl 2-chlorophenyl phenyl 2-methoxy H — SO₂ 2,5-thienyl 1-naphthyl phenyl 2-methoxy H — SO₂ 2,5-thienyl 1-(3,4-methylene phenyl dioxyphenyl) phenyl CH₃ R SO₂ 1,4-phenyl 2-fluorophenyl phenyl CH₃ R SO₂ 1,4-phenyl 2,6-dichlorophenyl phenyl CH₃ R SO₂ 1,4-phenyl 2,4-dichlorophenyl phenyl CH₃ R SO₂ 1,4-phenyl 2-trifluoromethyl phenyl phenyl CH₃ R SO₂ 1,4-phenyl 2,4,6-trimethyl phenyl phenyl CH₃ S SO₂ 1,4-phenyl 2-fluorophenyl phenyl CH₃ S SO₂ 1,4-phenyl 2,6-difluorophenyl phenyl CH₃ S SO₂ 1,4-phenyl 2,4-dichlorophenyl phenyl CH₃ S SO₂ 1,4-phenyl 2-trifluoromethyl phenyl phenyl CH₃ S SO₂ 1,4-phenyl 2,4,6-trimethylphenyl phenyl CH₃ Mix SO₂ 1,4-phenyl 2-methylphenyl phenyl CH₃ Mix SO₂ 1,4-phenyl 2-chlorophenyl phenyl CH₃ Mix SO₂ 1,4-phenyl 3-fluorophenyl 4-chlorophenyl CH₃ Mix SO₂ 1,4-phenyl 2-methylphenyl 4-chlorophenyl CH₃ Mix SO₂ 1,4-phenyl 2-chlorophenyl 4-chlorophenyl CH₃ Mix SO₂ 1,4-phenyl 3-fluorophenyl 4-chlorophenyl cyclo- — SO₂ 1,4-phenyl 2-methylphenyl propyl 4-chlorophenyl cyclo- — SO₂ 1,4-phenyl 2-chlorophenyl propyl 4-chlorophenyl cyclo- — SO₂ 1,4-phenyl 3-fluorophenyl propyl phenyl H — SO₂ 1,4-phenyl 2-methylphenyl phenyl H — SO₂ 1,4-phenyl 2-chlorophenyl phenyl H — SO₂ 1,4-phenyl 3-fluorophenyl phenyl CH₃ R SO₂ 1,4-phenyl phenyl phenyl CH₃ R SO₂ 1,4-phenyl 3-nitrophenyl phenyl CH₃ R SO₂ 1,4-phenyl 4-fluorophenyl phenyl CH₃ R SO₂ 1,4-phenyl 2-methylphenyl phenyl CH₃ R SO₂ 1,4-phenyl 3-trifluoromethyl phenyl phenyl CH₃ R SO₂ 1,4-phenyl 4-trifluoromethyl phenyl phenyl CH₃ R SO₂ 1,4-phenyl 3-chlorophenyl phenyl CH₃ R SO₂ 1,4-phenyl 3-methoxy phenyl phenyl CH₃ R SO₂ 1,4-phenyl 2-trifluoromethyl phenyl phenyl CH₃ R SO₂ 1,4-phenyl 2-methoxy phenyl phenyl CH₃ R SO₂ 1,4-phenyl 4-trifluoro methoxyphenyl phenyl CH₃ R SO₂ 1,4-phenyl 3-fluorophenyl phenyl CH₃ R SO₂ 1,4-phenyl 2-naphthyl phenyl CH₃ R SO₂ 1,4-phenyl 3-chloro-4- fluorophenyl phenyl CH₃ R SO₂ 1,4-phenyl 3-bromophenyl phenyl CH₃ R SO₂ 1,4-phenyl 4-chlorophenyl phenyl CH₃ R SO₂ 1,4-phenyl 3,5-dichloro phenyl phenyl CH₃ R SO₂ 1,4-phenyl 2,4-dichloro phenyl phenyl CH₃ R SO₂ 1,4-phenyl 3,5-ditrifluoro methylphenyl phenyl CH₃ R SO₂ 1,4-phenyl 2-benzofuryl phenyl CH₃ R SO₂ 1,4-phenyl 2-(t-butylamino sulfonyl)phenyl phenyl CH₃ R SO₂ 1,4-phenyl 4-cyanophenyl phenyl CH₃ R SO₂ 1,4-phenyl 3-cyanophenyl phenyl CH₃ R SO₂ 1,4-phenyl 3-carboxyphenyl phenyl CH₃ R SO₂ 1,4-phenyl 2[(di-i-propyl) aminocarbonyl] phenyl phenyl CH₃ R SO₂ 1,4-phenyl 4-(3,5-dimethyl) isoxazolyl phenyl CH₃ R SO₂ 1,4-phenyl 2-methoxy-5- formylphenyl phenyl CH₃ R SO₂ 1,4-phenyl 4-pyridyl phenyl CH₃ R SO₂ 1,4-phenyl 2,3,4-tri methoxyphenyl phenyl CH₃ R SO₂ 1,4-phenyl phenoxathiinyl phenyl CH₃ R SO₂ 1,4-phenyl 2-(5-formyl)furyl phenyl CH₃ R SO₂ 1,4-phenyl 2-(4-methyl) thienyl phenyl CH₃ R SO₂ 1,4-phenyl dibenzothienyl phenyl CH₃ R SO₂ 1,4-phenyl dianthrenyl phenyl CH₃ R SO₂ 1,4-phenyl dibenzothienyl phenyl CH₃ R SO₂ 1,4-phenyl 3-benzothienyl phenyl CH₃ R SO₂ 1,4-phenyl 3,4-dimethoxy phenyl phenyl CH₃ R SO₂ 1,4-phenyl 2-fluorophenyl phenyl CH₃ R SO₂ 1,4-phenyl 1-naphthyl phenyl CH₃ R SO₂ 1,4-phenyl 4-methoxy phenyl phenyl CH₃ R SO₂ 1,4-phenyl 3-fluoro-4- chlorophenyl phenyl CH₃ R SO₂ 1,4-phenyl 2-nitrophenyl phenyl CH₃ R SO₂ 1,4-phenyl 3-biphenyl phenyl CH₃ R SO₂ 1,4-phenyl 2-(t-butylcarbonyl amino)-3-methoxy phenyl phenyl CH₃ R SO₂ 1,4-phenyl 2-(t-butyl-carbonyl amino)-5-methoxy phenyl phenyl CH₃ R SO₂ 1,4-phenyl 2-(5-formyl)furyl phenyl CH₃ R SO₂ 1,4-phenyl 2,5-dimethoxy phenyl phenyl CH₃ R SO₂ 1,4-phenyl 2-(di(i-propyl) aminocarbonyl)-3- methoxyphenyl phenyl CH₃ R SO₂ 1,4-phenyl 4-methylthio phenyl phenyl CH₃ R SO₂ 1,4-phenyl 2,4,6-tri methylphenyl phenyl CH₃ R SO₂ 1,4-phenyl 3-methylphenyl phenyl CH₃ R SO₂ 1,4-phenyl 4-methylphenyl phenyl CH₃ R SO₂ 1,4-phenyl 3-pyridyl phenyl CH₃ R SO₂ 1,4-phenyl 3-aminophenyl phenyl CH₃ R SO₂ 1,4-phenyl 3-methylcarbonyl aminophenyl phenyl CH₃ R C(O) 1,4-phenyl 2-chlorophenyl phenyl CH₃ R C(O) 1,4-phenyl 2-methylphenyl phenyl CH₃ R C(O) 1,4-phenyl 3-fluorophenyl phenyl CH₃ R C(O) 1,4-phenyl 2-bromophenyl phenyl CH₃ R C(O) 1,4-phenyl 2,5-dichlorophenyl phenyl CH₃ R SO₂ 1,4-phenyl 2-methyl-3- chlorophenyl phenyl CH₃ R SO₂ 1,4-phenyl 2-chloro-5- methylphenyl phenyl CH₃ R SO₂ 1,4-phenyl 2-methyl-5- chlorophenyl phenyl CH₃ R SO₂ 1,4-phenyl 3-chloro-4- methylphenyl phenyl CH₃ R SO₂ 1,4-phenyl 2-chloro-6- methylphenyl phenyl CH₃ R SO₂ 1,4-phenyl 2-chloro-4- methylphenyl 3-trifluoro H — SO₂ 1,4-phenyl phenyl methylphenyl phenyl CH₃ R C(O)NH 1,4-phenyl phenyl phenyl CH₃ S C(O)NH 1,4-phenyl phenyl


25. The compound of claim 1 of the formula

wherein R⁴, m, R⁵, R⁶, Y and the stereospecificity are selected in concert from the group consisting of: R⁴ m R⁵ R⁵ Stereo Y 1,5-n-pentyl 1 phenyl CH₃ R 2-methylphenyl 1,5-n-pentyl 1 phenyl CH₃ R 2-chlorophenyl 1,5-n-pentyl 1 phenyl CH₃ R 3-fluorophenyl 1,5-n-pentyl 1 phenyl CH₃ S 2-methylphenyl 1,5-n-pentyl 1 phenyl CH₃ S 2-chlorophenyl 1,5-n-pentyl 1 phenyl CH₃ S 3-fluorophenyl 1,5-n-pentyl 1 2-methoxy- H — 2-methylphenyl phenyl 1,6-n-hexyl 1 2-methoxy- H — 2-chlorophenyl phenyl 1,6-n-hexyl 1 2-methoxy- H — 2-methoxyphenyl phenyl 1,6-n-hexyl 1 2-methoxy- H — 2,4-dichlorophenyl phenyl 1,6-n-hexyl 0 2-methoxy- H — 2-methylphenyl phenyl 1,6-n-hexyl 0 2-methoxy- H — 2-chlorophenyl phenyl 1,6-n-hexyl 0 2-methoxy- H — 2-methoxyphenyl phenyl 1,6-n-hexyl 0 2-methoxy- H — 2,4-dichlorophenyl phenyl 1,6-n-hexyl 1 phenyl CH₃ R 2-methylphenyl 1,6-n-hexyl 1 phenyl CH₃ R 2-chlorophenyl 1,6-n-hexyl 1 phenyl CH₃ R 3-fluorophenyl 1,6-n-hexyl 1 phenyl CH₃ S 2-methylphenyl 1,6-n-hexyl 1 phenyl CH₃ S 2-chlorophenyl 1,6-n-hexyl 1 phenyl CH₃ S 3-fluorophenyl


26. The compound of claim 1 of the formula

wherein R⁴, R⁵,

and X are selected in concert from the group consisting of: R⁴ R⁵

X 1,4-n-butyl 2-methoxyphenyl 1-phenyl 2,3-dichloro 1,6-n-hexyl 2-methoxyphenyl 1-phenyl 2,3-dichloro 1,4-n-butyl 3,4-methylenedioxyphenyl 8-quinolinyl — 1,6-n-hexyl 3,4-methylenedioxyphenyl 8-quinolinyl —


27. The compound of claim 1 of the formula

wherein m and Y are selected in concert from the group consisting of: m Y 1 2-methylphenyl 1 3-thienyl 1 2-methoxyphenyl 1 4-fluorophenyl 1 2,4-dimethoxyphenyl 1 4-methoxyphenyl 1 4-methylphenyl 1 1-naphthyl 1 2-chlorophenyl 1 3-pyridyl 1 2-thienyl 1 3-acetamidophenyl 1 phenyl 1 4-chlorophenyl 1 4-[3,5-dimethylisoxazolyl] 1 3-chlorophenyl 1 4-cyanophenyl 1 4-pyridyl 1 3-methoxyphenyl 1 3-aminophenyl 1 3-fluorophenyl 1 2-fluorophenyl 1 3,4-methylenedioxyphenyl 0 2-methylphenyl 0 3-thienyl 0 2-methoxyphenyl 0 4-fluorophenyl 0 2,4-dimethoxyphenyl 0 4-methoxyphenyl 0 4-methylphenyl 0 1-naphthyl 0 2-chlorophenyl 0 3-pyridyl 0 2-thienyl 0 3-acetamidophenyl 0 phenyl 0 4-chlorophenyl 0 4-[3,5-dimethylisoxazolyl] 0 3-chlorophenyl 0 4-cyanophenyl 0 4-pyridyl 0 3-methoxyphenyl 0 3-aminophenyl 0 3-fluorophenyl 0 2-fluorophenyl 0 3,4-methylenedioxyphenyl


28. The compound of claim 1 of the formula

wherein R⁵,

and X are selected in concert from the group consisting of: R⁵

X 2-methoxyphenyl 1-phenyl 2,3-dichloro 3,4-methylenedioxyphenyl 8-quinolinyl —


29. The compound of claim 1 of the formula

wherein Y and the stereospecificity are selected in concert from the group consisting of: Stereo Y R 2-methylphenyl R 2-chlorophenyl R 3-fluorophenyl S 2-methylphenyl S 2-chlorophenyl S 3-fluorophenyl and stereoisomers and pharmaceutically acceptable salts or esters thereof.


30. The compound of claim 1 of the formula

wherein Y is from the group consisting of: Y 2-methylphenyl 2-chlorophenyl 3-fluorophenyl and stereoisomers and pharmaceutically acceptable salts or esters thereof.


31. The compound of claim 1 of the formula

wherein X and n and the stereospecificity are selected in concert from the group consisting of: Stereo n X R 1 4-n-butyl R 0 — R 1 4-bromo S 1 4-bromo R 1 4-methoxy R 1 4-trifluoromethyl R 1 4-isopropyl R 1 4-n-propyl R 1 4-t-butyl R 1 4-n-pentyl R 1 3-methoxy S 1 4-methoxy S 1 4-trifluoromethyl S 1 4-isopropyl S 1 4-n-propyl S 1 4-t-butyl S 1 4-n-pentyl S 1 3-methoxy and stereoisomers and pharmaceutically acceptable salts or esters thereof.


32. The compound of claim 1 of the formula

wherein R¹, R², Y and the stereospecificity are selected in concert from the group consisting of: R¹ R² Stereo Y methyl methyl R 2-chlorophenyl ethyl ethyl R 2-chlorophenyl H methylcarbonyl R 2-chlorophenyl methyl methyl S 2-methylphenyl ethyl ethyl S 2-methylphenyl H methylcarbonyl S 2-methylphenyl and stereoisomers and pharmaceutically acceptable salts or esters thereof.


33. The compound of claim 1 of the formula

wherein R⁴ and L are selected in concert from the group consisting of R⁴ L —CH₂-(1,4-phenyl)-CH₂— 4-methyoxyphenylethyl —CH₂-(1,4-phenyl)-CH₂— 3,6-dimethoxyphenylethyl —CH₂-(1,4-phenyl)-CH₂— 2,3-dimethoxyphenylethyl —CH₂-(1,4-phenyl)-CH₂— 1-cyclohexenylethyl —CH₂-(1,4-phenyl)-CH₂— 3-bromo-4,5-dimethylphenylethyl —CH₂-(1,4-phenyl)-CH₂— 2-chlorphenylethyl —CH₂-(1,4-phenyl)-CH₂— 3-chlorophenylethyl —CH₂-(1,4-phenyl)-CH₂— 2,4-dichlorophenylethyl —CH₂-(1,4-phenyl)-CH₂— 2,6-dichlorophenylethyl —CH₂-(1,4-phenyl)-CH₂— 2-trifluoromethylphenylethyl —CH₂-(1,4-phenyl)-CH₂— 3,4-dimethylphenylethyl —CH₂-(1,4-phenyl)-CH₂— 3,5-dimethylphenylethyl —CH₂-(1,4-phenyl)-CH₂— 3-methoxyphenylethyl —CH₂-(1,4-phenyl)-CH₂— 3-(2-chlorophenyl)-4,5- dimethoxyphenylethyl n-hexyl 3,4-dimethoxyphenylethyl n-hexyl 4-methoxyphenylethyl n-hexyl 2,3-dimethoxyphenylethyl n-hexyl 3-bromo-4,5- dimethoxyphenylethyl n-hexyl 2-chlorophenylethyl n-hexyl 3-chlorophenylethyl n-hexyl 2,4-dichlorophenylethyl n-hexyl 2,6-dichlorophenylethyl n-hexyl 3,5-dimethoxyphenylethyl n-hexyl 3-methoxyphenylethyl n-hexyl 2,5-dimethoxyphenylethyl n-hexyl 1-cyclohexenylethyl n-hexyl 3-(2-chlorophenyl)-3,4- dimethoxyphenylethyl n-hexyl 2-fluorophenylethyl n-hexyl 2-trifluoromethylphenylethyl —CH₂-(1,4-phenyl)-CH₂— 2-nitrophenylethyl —CH₂-(1,4-phenyl)-CH₂— 2-aminophenylethyl —CH₂-(1,4-phenyl)-CH₂— 2-dimethylaminophenylethyl —CH₂-(1,4-phenyl)-CH₂— 2-(methylcarbonylamino) phenylethyl —CH₂-(1,4-phenyl)-CH₂— 2-(methylsulfonylamino) phenylethyl —CH₂-(1,4-phenyl)-CH₂— CH₂—C(CH₃)₂-phenyl —CH₂-(1,4-phenyl)-CH₂— CH₂—C(OCH₃)-phenyl —CH₂-(1,4-phenyl)-CH₂— CH₂—CH(CH₃)-(2-methoxyphenyl) —CH₂-(1,4-phenyl)-CH₂— bicyclo[4.2.0]octa-1,3,5-triene —CH₂-(1,4-phenyl)-CH₂— CH₂—CH(cyclohexyl)-phenyl —CH₂-(1,4-phenyl)-CH₂— CH₂—CH(cyclobutyl)-phenyl —CH₂-(1,4-phenyl)-CH₂— CH₂—CH(ethyl)-phenyl —CH₂-(1,4-phenyl)-CH₂— 2,3-dihydro-1H-indene —CH₂-(1,4-phenyl)-CH₂— CH(phenyl)₂ —CH₂-(1,4-phenyl)-CH₂— 2-methylphenylethyl —CH₂-(1,4-phenyl)-CH₂— 3-fluorophenylethyl —CH₂-(1,4-phenyl)-CH₂— 3,4-methylenedioxy phenyl —CH₂-(1,4-phenyl)-CH₂— 2-pyridylethyl —CH₂-(1,4-phenyl)-CH₂— 2-thienylethyl —CH₂-(1,4-phenyl)-CH₂— 2-(N-methyl)-pyrrolidinylethyl —CH₂-(1,4-phenyl)-CH₂— phenylpropyl —CH₂-(1,4-phenyl)-CH₂— 2-ethoxyphenylethyl —CH₂-(1,4-phenyl)-CH₂— 3,4-dichlorophenylethyl n-hexyl CH₂—CH(OCH₃)-phenyl n-hexyl CH₂—CH(CH₃)-(2-methoxyphenyl) n-hexyl bicyclo[4.2.0]octa-1,3,5-triene n-hexyl CH₂—CH(cyclohexyl)-phenyl n-hexyl CH₂—CH(cyclobutyl)-phenyl n-hexyl CH₂—CH(ethyl)-phenyl n-hexyl 2,3-dihydro-1H-indene n-hexyl CH₂—CH(phenyl)₂ n-hexyl 2-methylphenylethyl n-hexyl 3-fluorophenylethyl n-hexyl 3,4-methylenedioxyphenyl n-hexyl 2-pyridylethyl n-hexyl 2-thienylethyl n-hexyl 2-(N-methylpyrrolidinyl)ethyl n-hexyl phenylpropyl n-hexyl 2-ethoxyphenylethyl n-hexyl 3,4-dichlorophenylethyl n-hexyl 3-trifluoromethylphenylethyl and stereoisomers and pharmaceutically acceptable salts or esters thereof.


34. The compound of claim 1 of the formula

wherein Y and the stereospecificity are selected in concert from the group consisting of: Stereo Y R 2-chlorophenyl R 2-methylphenyl R 3-fluorophenyl S 2-chlorophenyl and stereoisomers and pharmaceutically acceptable salts or esters thereof.


35. The compound of claim 1, selected from the group consisting of


36. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim
 1. 37. A process for making a pharmaceutical composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier.
 38. A method of treating a condition or disorder mediated by the FSH receptor, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of claim
 1. 39. A method of treating a condition or disorder selected from the group consisting of uterine fibroids, endometriosis, polycystic ovarian disease, dysfunctional uterine bleeding, breast cancer and ovarian cancer; depletion of oocytes; spermatocyte depletion; or for female and male contraception, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim
 1. 40. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1, for the preparation of a medicament for the treatment of a condition or disorder selected from the group consisting of uterine fibroids, endometriosis, polycystic ovarian disease, dysfunctional uterine bleeding, breast cancer and ovarian cancer; depletion of oocytes; spermatocyte depletion; or for female and male contraception. 